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Flavonoids- Apple A Day Improves Brain(prevent Parkinsons) & Orange A Day Improves Inflammation-CVD
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Download the PDF here
Download the PDF here
An Orange a Day Keeps Stroke Away & Improves Inflammation & Perhaps Neuroinflammation - (02/27/12)
"oranges are a richer source of flavanones.......Over 14 years of follow-up, high flavanone intake was associated with a 19% lower risk of ischemic stroke.....high intake of citrus fruits/juice tended to be associated with a reduced risk of ischemic stroke (RR, 0.90; 95% CI, 0.77-1.05; Q5 versus Q1). Citrus fruits and juices contain other constituents that may reduce the risk of stroke, including vitamin C and potassium"
An apple a day to prevent Parkinson disease - editorial
Reduction of risk by flavonoids
Walter Kukill PhD
From the Department of Epidemiology, University of Washington, Seattle.
Experimental studies have shown that after oral administration of a blueberry or strawberry extract, anthocyanin concentrations were significantly increased in the brain, reaching concentrations that were much higher than in peripheral tissues.10 Oral administration of blueberry or strawberry extract in 11 animal studies showed consistent favorable neuroprotective effects including increasing dopamine release, alleviating oxidative stress, and suppressing neuroinflammation.10 Anthocyanins have been found to induce detoxifying enzymes which may play an important role in PD etiology.......In this large prospective study, we found that participants with greater consumption of anthocyanins, quercetin, epicatechin, and some proanthocyanidins were less likely to develop PD during 20-22 years of follow-up. Higher intakes of anthocyanin-rich foods, such as berries, were associated with lower PD risk. When we combined all individual flavonoids together, total flavonoid intake was also associated with a significantly lower PD risk in men but not in women......Higher intakes of total flavonoids were significantly associated with a lower risk of PD in men (p trend = 0.001), but not in women (p trend = 0.62).....Flavonoid-rich food (tea, apples, blueberries/strawberries, red wine, oranges/orange juice)......We further analyzed the top 5 major flavonoid-rich foods in relation to PD risk (table 4). Consistent with our subclass analyses, greater intake of berries, which are rich in anthocyanins, but not of tea, red wine, and orange/orange juice, were significantly associated with a lower risk of developing PD (p trend = 0.007) in the pooled analyses. Apple intake was also associated with a decreased risk in men (p trend < 0.0001) but not in women (p trend = 0.31).
The search for environmental risk factors for Parkinson disease (PD) has yielded few potentially causal associations.1 The recognition of genetic factors in the etiology of PD,2,3 in conjunction with PD pathology, has led to the suggestion that PD results from abnormal α-synuclein, its propagation, eventual deposition as Lewy bodies, and subsequent neurodegeneration.4,5 The potential role of oxidative damage in this process, possibly through mitochondrial insult by environmental toxins,6 has provided additional leads for the effects of environmental factors, notably pesticides.7 The search for environmental factors is made more difficult as the pathology is likely to have begun many years prior to the diagnosis of PD.1
The rarity of PD,8 about 100 per 100,000 in the oldest age groups, presents a challenge for epidemiologic study. A longitudinal cohort study, starting with unaffected persons, requires large numbers and long follow-up to accrue an adequate number of cases for analysis. Another key requirement is reliable and accurate measurement of the hypothesized exposures, at baseline and throughout the study. Further, because "clinical incidence" may occur many years after pathology begins, it is important to consider when the exposure must have happened in order to cause the disease. Unfortunately, we do not know what that critical exposure time window is, or how it may differ depending on the exposed agent. The causal effect of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)9 is rapid as compared to the possible protective effect associated with cigarette smoking.1 Whether long-term, low-level exposures would sum to exert a cumulative effect is uncertain; some exposures at low levels may simply be insufficient to promote the disease process.
In this issue of Neurology®, Gao et al.10 analyzed data from 2 large cohort studies addressing whether dietary flavonoid intake might influence the onset of PD. The Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) used similar methods but were conducted separately. The NHS began in 1976, and with 121,700 female registered nurses, 80,366 beginning with a 1984 baseline visit were included in this analysis. The HPFS began in 1986 and enrolled 51,529 male health professionals; 49,281 with a baseline 1986 visit were included in the present analysis. From among these cohorts, 805 incident PD cases occurred during 20-22 years of follow-up (about 20.1 and 42.5 cases per 100,000 person-years, in the NHS and HPFS). Self-report questionnaires were completed to capture incident PD (verified by medical records) and food frequency questionnaires were completed at baseline and subsequently every 4 years to report average food intake (type and amount) during the previous year. Flavonoid content was inferred based on standard content analyses.
Flavonoid-rich food (tea, apples, blueberries/strawberries, red wine, oranges/orange juice) were captured as servings per week and then categorized into 6 subclasses of flavonoids, then further divided into about 30 flavonoid compounds. Quintiles of consumption were tested for their association with risk of PD and for any dosage trends. To ensure that flavonoid values might reflect consumption before clinical onset of PD only average cumulative intake up to 4 years prior to clinical onset was used.
In the primary analysis, after multivariate adjustment, including age and smoking, there was a decreased risk of PD in men for the fourth and fifth quintiles of total flavonoid intake and a significant trend suggesting a dose-response effect, with the decreased risk only in the HPFS and not in the NHS. This heterogeneity would argue against "pooling" the 2 datasets for analysis. Because the NHS is comprised of only women and the HPFS is only men, perhaps the difference indicates effect modification by sex rather than an effect of study differences; we cannot be sure. Examining flavonoid subclasses, only flavonols, polymers, and possibly anthocyanins were associated with decreased risk in men. Men who ate 5 or more servings of apples per week had a decreased risk of PD compared to those who eat less than 1 apple per month, but the same is not true among women in the NHS. Aside from the trend tests most quintile hazard ratios 95% confidence intervals include the null, for all exposure measures in both men and women.
Could there be a sex-specific difference in the way that flavonoids might be metabolized or might act to influence PD pathology? The Cytochrome P-450 enzyme system is affected by aging and has sex-dependent metabolic differences.11 Flavonoid compounds hesperetin and diosmetin at relatively high levels can inhibit drug metabolism (e.g., nonsteroidal anti-inflammatory drugs, warfarin, metronidazole, midazolam) by CYP2C9 and CYP3A4/5.12 Could these biotransformation enzymes provide some clues as to the mechanisms of action leading to different effects in men and women? These are tantalizing biological avenues that require additional research.
Despite the care taken by researchers in studies such as these, primary exposures determined by self-report, even with well-validated questionnaires, may result in misclassification. Would the same food frequency questionnaire be filled out systematically differently by men and women? Would those who were prone to report higher flavonoid consumption also be those less likely, in the future, be diagnosed with PD? After adjustment for a variety of factors, it would seem unlikely that a differential misclassification caused a biased estimate of risk. Conversely, we may worry that the many subclasses and compounds tested based on the report of food frequency create a multiple testing issue. Uncontrolled confounding may also exist. We await additional research to address these issues; until then, an apple a day might be a good idea.
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Habitual intake of dietary flavonoids and risk of Parkinson disease
Abstract
Objective: To prospectively examine whether higher intakes of total flavonoids and their subclasses (flavanones, anthocyanins, flavan-3-ols, flavonols, flavones, and polymers) were associated with a lower risk of developing Parkinson disease (PD).
Methods: In the current analysis, we included 49,281 men in the Health Professional Follow-up Study and 80,336 women from the Nurses' Health Study. Five major sources of flavonoid-rich foods (tea, berry fruits, apples, red wine, and orange/orange juice) were also examined. Flavonoid intake was assessed using an updated food composition database and a validated food frequency questionnaire.
Results: We identified 805 participants (438 men and 367 women) who developed PD during 20-22 years of follow-up. In men, after adjusting for multiple confounders, participants in the highest quintile of total flavonoids had a 40%lower PD risk than those in the lowest quintile (hazard ratio [HR] = 0.60; 95% confidence interval 0.43, 0.83; p trend = 0.001). No significant relationship was observed in women (p trend = 0.62) or in pooled analyses (p trend = 0.23). In the pooled analyses for the subclasses, intakes of anthocyanins and a rich dietary source, berries, were significantly associated with a lower PD risk (HR comparing 2 extreme intake quintiles were 0.76 for anthocyanins and 0.77 for berries, respectively; p trend < 0.02 for both).
Conclusions: Our findings suggest that intake of some flavonoids may reduce PD risk, particularly in men, but a protective effect of other constituents of plant foods cannot be excluded.
GLOSSARY
BBB=blood-brain barrier;
BMI=body mass index;
CI=confidence interval;
FFQ=food frequency questionnaire;
HPFS=Health Professionals Follow-up Study;
HR=hazard ratio;
NHS=Nurses' Health Study;
PD=Parkinson disease
Flavonoids are widely distributed in many plant-based foods/beverages.1 Historically, their biological effects were attributed to antioxidant actions,2 but recent evidence suggests that this classic hydrogen-donating antioxidant activity cannot account for their in vivo bioactivity, particularly in the brain where they are found in low concentrations.3,4 Other relevant potential mechanisms include interactions with neuronal signaling pathways that are critical in controlling neuronal survival and differentiation and in modulating activity/expression of several oxidative-related enzymes (e.g., eNOS and SOD),4,5 and regulation of mitochondrial function or neuroinflammation.4,-,6 In experimental studies, administration of flavonoids or flavonoid-rich foods (e.g., berry fruits) protected dopamine neurons from oxidative damage and apoptosis and inhibited formation of α-synuclein fibrils.7,-,10
Because of these properties, it has been suggested that flavonoids (or their metabolites) that pass through the blood-brain barrier (BBB)11,12 could reduce Parkinson disease (PD) risk. However, the metabolic alteration of flavonoids following ingestion is considerable,1,13,14 and there are no convincing human data on whether diets high in flavonoids have neuroprotective effects. We therefore conducted the first prospective study to examine whether greater intakes of total flavonoid or their subclasses (i.e., flavanones, anthocyanins, flavan-3-ols, flavonols, flavones, and polymers) lowered risk of developing PD. We also examined the association between major flavonoid-rich foods and PD risk.
RESULTS
During 20-22 years of follow-up (mean follow-up was 20.0 years for men and 22.7 years for women), we documented 805 incident PD cases (438 men and 367 women). Participants with higher flavonoid intake were older and less likely to be current smokers, reported lower intakes of lactose and alcohol, reported higher intakes of vitamin C and beta-carotene, and had a healthier diet quality, as assessed by the alternate healthy eating index (table 1).Higher intakes of total flavonoids were significantly associated with a lower risk of PD in men (p trend = 0.001), but not in women (p trend = 0.62) (table 2). The multivariable adjusted HRs for the highest vs lowest quintile of total flavonoid intake were 0.60 (95% CI 0.43-0.83) for men and 1.01 (95% CI 0.70-1.44) for women. The pooled HR was 0.77 (95% CI 0.46-1.28; p trend = 0.23; p heterogeneity = 0.02). The associations between total flavonoids and PD risk were similar for those with relative younger onset of PD (<70 y) and those with onset 70+ y (data not shown). In the analyses of flavonoid subclasses (table 3), we found a significant association between greater anthocyanin intake and lower PD risk: the pooled HR comparing the 2 extreme intake quintiles was 0.76 (95% CI 0.61-0.96; p trend = 0.02; p heterogeneity = 0.83). Other flavonoid subclasses were not significantly associated with PD risk, with the exception of the polymeric forms in men. We also observed a significant trend toward greater consumption of flavonols and lower risk of PD in men (p trend = 0.01) although the HR comparing the 2 extreme intake quintiles was not significant. We then investigated PD risk according to intake of each individual flavonoid compound (table e-1 on the Neurology® Web site at www.neurology.org). In the pooled analyses, higher intake of the flavonol, quercetin, the anthocyanins, cyanidin, and pelargonidin and 2 flavan-3-ol monomers and polymers (epicatechin and proanthocyanidindimers) were significantly associated with lower risk of PD in the pooled analysis (p < 0.05 for all).
Higher intakes of total flavonoids were significantly associated with a lower risk of PD in men (p trend = 0.001), but not in women (p trend = 0.62) (table 2). The multivariable adjusted HRs for the highest vs lowest quintile of total flavonoid intake were 0.60 (95% CI 0.43-0.83) for men and 1.01 (95% CI 0.70-1.44) for women. The pooled HR was 0.77 (95% CI 0.46-1.28; p trend = 0.23; p heterogeneity = 0.02). The associations between total flavonoids and PD risk were similar for those with relative younger onset of PD (<70 y) and those with onset 70+ y (data not shown). In the analyses of flavonoid subclasses (table 3), we found a significant association between greater anthocyanin intake and lower PD risk: the pooled HR comparing the 2 extreme intake quintiles was 0.76 (95% CI 0.61-0.96; p trend = 0.02; p heterogeneity = 0.83). Other flavonoid subclasses were not significantly associated with PD risk, with the exception of the polymeric forms in men. We also observed a significant trend toward greater consumption of flavonols and lower risk of PD in men (p trend = 0.01) although the HR comparing the 2 extreme intake quintiles was not significant. We then investigated PD risk according to intake of each individual flavonoid compound (table e-1 on the Neurology® Web site at www.neurology.org). In the pooled analyses, higher intake of the flavonol, quercetin, the anthocyanins, cyanidin, and pelargonidin and 2 flavan-3-ol monomers and polymers (epicatechin and proanthocyanidindimers) were significantly associated with lower risk of PD in the pooled analysis (p < 0.05 for all).
We further analyzed the top 5 major flavonoid-rich foods in relation to PD risk (table 4). Consistent with our subclass analyses, greater intake of berries, which are rich in anthocyanins, but not of tea, red wine, and orange/orange juice, were significantly associated with a lower risk of developing PD (p trend = 0.007) in the pooled analyses. Apple intake was also associated with a decreased risk in men (p trend < 0.0001) but not in women (p trend = 0.31).
Similar results were obtained in all sensitivity analyses. When we used the cumulative average intake of flavonoids as exposures, the multivariate HRs were 0.65 (95% CI 0.46-0.91; p trend = 0.01) for total flavonoids in men and 1.08 (95% CI 0.74-1.56; p trend = 0.64) in women. The pooled HR was 0.69 (95% CI 0.54-0.88; p trend = 0.002) for anthocyanin intake. Even when we further adjusted for the Alternate Healthy Eating Index (comprised of fruit, vegetables, nuts and soy, and other dietary components)20 and the dietary urate index (comprised of intake of fructose, vitamin C, alcohol, and dairy protein),23 the associations did not change materially: the HRs were 0.61 (95% CI 0.44-0.85; p trend = 0.003) for total flavonoids in men and 1.04 (95% CI 0.72-1.51; p trend = 0.68) in women and the pooled HR was 0.80 (95% CI 0.63-1.02; p trend = 0.05) for anthocyanin intake. Restricting to neurologist-diagnosed cases did not materially change the results (p trend < 0.05 for total flavonoids in men and antocyanin in the pooled analysis). Further including PD cases not confirmed by treating physicians or review of medical record attenuated the associations: the HRs were 0.67 (p trend = 0.005) for total flavonoids in men and 1.05 (p trend = 0.95) in women and the pooled HR was 0.90 (p trend = 0.16) for anthocyanin intake. Using the original continuous dietary intake variables for trend test generated similar results (data not shown). Finally, we observed no significant interactions between total flavonoids and age, smoking, caffeine, or alcohol intake (p interaction > 0.3 for all).
DISCUSSION
In this large prospective study, we found that participants with greater consumption of anthocyanins, quercetin, epicatechin, and some proanthocyanidins were less likely to develop PD during 20-22 years of follow-up. Higher intakes of anthocyanin-rich foods, such as berries, were associated with lower PD risk. When we combined all individual flavonoids together, total flavonoid intake was also associated with a significantly lower PD risk in men but not in women.
Our observation that a higher intake of anthocyanins and anthocyanins-rich foods were associated with a lower risk of PD are consistent with a previous case-control study, where PD patients (n = 81) were found to be ~40%-60% less likely to consume blueberries or strawberries, compared to controls.24 Experimental studies have shown that after oral administration of a blueberry or strawberry extract, anthocyanin concentrations were significantly increased in the brain, reaching concentrations that were much higher than in peripheral tissues.10 Oral administration of blueberry or strawberry extract in 11 animal studies showed consistent favorable neuroprotective effects including increasing dopamine release, alleviating oxidative stress, and suppressing neuroinflammation.10 Anthocyanins have been found to induce detoxifying enzymes which may play an important role in PD etiology.25 In a recent animal study of PD, intake of the anthocyanin pelargonidin dose-dependently attenuated behavioral and structural abnormalities due to 6-OHDA toxicity and decreased lipid peroxidation.26
It is established that anthocyanins can cross the BBB in rodents and in pigs following ingestion of anthocyanins-rich diets.27 In vitro and animal studies have also shown that the flavanones and their in vivo metabolites can cross the BBB and oral administration of tea to mice identified levels of epicatechin metabolites in brain tissue.28 However, different flavonoid subclasses differ in their ability to cross the BBB and these differences depend in part on the lipophilicity and polarity of the flavonoid compound.12,29 During absorption they are extensively metabolized, with chemical transformations resulting in O-methylation and glucuronidation during phase II metabolism which may have a significant impact on flavonoid bioavailability to the brain. Further transformation has been reported in the colon where the intestinal microflora degrade flavonoids to simple phenolic acids.1,13 It is therefore possible that the less polar O-methylated metabolites, for example O-methylated epicatechin metabolites, which are formed in the small intestine and liver, may be more bioavailable to the brain than their parent aglycones.12
We observed that greater intakes of epicatechin and proanthocyanidindimers (i.e., dimers of the monomeric flavan-3-ol subclass) were associated with lower PD risks. Previous experimental studies reported that dietary epicatechin stimulated the phosphorylation of the transcription factor cAMP-response element binding protein, a regulator of neuronal viability and synaptic plasticity, and inhibited NADPH oxidase activity.30,31 Recent data suggest that the neuroprotective mechanisms of the flavan-3-ol, epigallocatechin-3-gallate, relate to regulation of neuroinflammation and modulation of genes involved in cell survival and death by decreasing intracellular calcium levels and controlling NO production.32 Oral administration of proanthocyanidins in rats significantly increased brain dopamine concentrations, inhibited monoamine oxidase-A activity, and attenuated the 6-OHDA-induced dopaminergic loss.33,34 Interestingly, proanthocyanidins may not be able to cross the BBB due to their high molecular weight, but following ingestion they are extensively metabolized, with degradation to simple phenolic acids accruing in the large intestine,13,14 and recently these simple phenolic acids have been shown to protect neurons in vitro against injury induced by 5-s-cysteinyl-dopamine at a similar magnitude to the effects of the aglycones.6 It is thus important to examine in future proanthocyanidin studies the relative importance of the range of in vivo metabolites on neuroprotection.
We did not find a significant association between consumption of flavonols and flavones and PD risk. However, greater intake of the flavonol quercetin may be associated with lower PD risk. In previous animal and in vitro studies, quercetin has been found to exert a neuroprotective effect against oxidative stress and neuron loss induced by MPP+ or 6-OHDA,35,36 although high dose could be neurotoxic.37 However, no human studies have been conducted to examine effects of quercetin on PD risk to date. In a population-based study, patients with PD (n = 31) and controls reported similar dietary intake of flavonols and flavones (27.5 vs 28.5 mg/day).38 However, this study did not differentiate quercetin from other flavonoids and was limited by its cross-sectional design and small sample size. Further studies are therefore needed to replicate our observations.
The association between total flavonoid intake and PD risk was more pronounced in men than women. This difference seems unlikely to be due to the higher intake of flavonoid in women, because we observed a similar nonsignificant result in women when we regrouped them using the men's quintile cutoff points for flavonoid intakes (data not shown). In previous studies, a similar gender difference has been reported for several risk/protective factors of PD. For example, the significant inverse associations between caffeine intake, plasma urate, and risk of PD have been observed only in men, but not in women.19,23,39,40 However, it is unclear if this gender difference in the effects of flavonoids on PD risk reflects a true biological difference or is driven by chance because we did not observe such gender difference when we examined the subclasses of flavonoid in relation to risk of PD. Further, the interaction between total flavonoids and use of estrogen was not significant in women (p interaction = 0.63).
Because of our prospective design, our study is unlikely to be affected by recall and selection biases. Conversely, misclassification of flavonoid intake is inevitable, because of errors in reporting food consumption, and incompleteness of existing databases that only list the most common among several hundreds of flavonoids. However, there are currently no reliable biomarkers of flavonoid intake to integrate intake with the extensive metabolism that occurs following ingestion. Because the study population was primarily white health professionals, the results might not be generalizable to all populations. However, this homogeneity of social educational status helps to reduce some confounding and enhances the internal validity. Finally, as with any observational study, we cannot exclude the possibility of residual confounding. Although we controlled for a range of diet and lifestyle factors, it remains possible that other constituents of fruits and vegetables confound the association between flavonoids and PD risk. Because of these limitations, the results presented here should be interpreted cautiously and need to be confirmed in other large prospective studies, preferably in populations with wide heterogeneity in flavonoid content.
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