August 2001, Volume 23, No. 8
Discussion Paper

The role of antioxidants in dementia and other diseases: a review

V S F Chow 周修芳

HK Pract 2001;23:344-351

Summary

A lot of research had been done to investigate the preventive and treatment roles of antioxidants in different diseases. A review of recently published papers was done. Well-known antioxidants are Vitamins A, C and E. They are rich in fruits and vegetables. Vitamin E is postulated to be beneficial in treatment of dementia, while the use of ginkgo biloba is still controversial. Epidemiological evidence has shown protective role of antioxidants in coronary heart disease and cancer, but clinical trials did not. Some other substances in fruits and vegetables might play a more important role. Therefore, further investigations may be needed. It might be beneficial to advise public to increase the consumption of fruits and vegetables in this context.

摘要

人們對抗氧化劑對不同疾病的預防和治療作用做 了大量研究，本文回顧了近期發表的論文。蔬果、水 果含有豐富的維他命A 、C 、E ，它們都是為人熟悉 的抗氧化劑。維他命E 對冶療老年性痴呆症有一定益 處，而銀杏葉的使用則仍有爭議性。流行病學研究證 明抗氧化劑對心臟病和癌病有預防作用，但臨床試驗 卻未能證實。蔬菜、水果所含有的其他成份可能有更 重要的作用，需要進一步研究。目前，應提倡多進食 水果蔬菜類食物。

Introduction

Currently, antioxidant is a popular nutritional and medical topic. An antioxidant is any substance that is able to protect against the damages of oxidative stress caused by reactive oxygen species such as free radicals. Free radical is an atom or molecule containing one or more unpaired electron. It is chemically very reactive and has a potential to cause extensive damage to the organism.1 Well-known antioxidants are Vitamins A, C and E, all of which are readily found in fruits and vegetables. (Please refer to Table 1 for the Dietary Reference Values2 and food source3). A lot of research had been done to investigate the preventive and treatment roles of antioxidants in different diseases. The findings are valuable for promoting good health. Based on the literature, this review paper attempts to discuss the roles of antioxidants on the following diseases:

  • Dementia, with discussion on the treatment role of Vitamin E and the controversial role of ginkgo biloba
  • Parkinson's disease (PD)
  • Coronary heart disease (CHD), and
  • Cancer

Moreover, the discrepancies found between the results of epidemiological studies and those of clinical trials on the effectiveness of antioxidants in the above diseases are also addressed. The discussion on dementia in this paper will outweigh those on other diseases.

Antioxidant and dementia

Many studies showed that there is a relationship between antioxidants and dementia.4,5 The histopathological changes in Alzheimer's disease (AD) include neuronal cell death and formation of amyloid plaques. There is evidence that brain tissues in patients with AD are exposed to oxidant stress during the course of the disease. Antioxidants are likely to scavenge free radicals.6,7

Can dementia be prevented by dietary means?

Abbott8 had conducted a series of mental performance tests in a group of 3,733 elderly Japanese-American men living in Hawaii during 1991-93. Many of these men had experienced poor, malnutrition childhood in Japan, and migrated to Hawaii during adulthood. The prevalence of poor mental performance declined consistently with increasing height. In addition, Alzheimer's disease (AD) was much more prevalent in the shortest group (4.7%) compared with men in the tallest group (2.9%). Poor childhood nutrition would lead to height deficits. Thus, shortness may reflect deficits in brain growth and development due to a poor diet.

Vitamin E and dementia

Vitamin E is the only lipid-soluble, chain-breaking antioxidant in biological membranes. Vitamin E may play a role in the treatment of some disorders in which oxidative stress has been implicated such as dementia.

Sano et al9 conducted a two-year double-blind, placebo controlled, randomised, multi-centre clinical trial involving 341 patients with AD of moderate severity. Subjects were randomised into four groups: placebo group, Vitamin E (2,000 iμ/d) group, selegiline (10 mg/d) group or a combination of Vitamin E and selegiline. When Mini-Mental State Examination was used as a covariate, median survival increased significantly in the treated group compared with the placebo group. The author concludes that treatment with Vitamin E and selegiline slowed the progress of AD and delayed deterioration of function and thus the need for institutionalisation. In Honolulu Heart Program, Masaki et al10 also found supplementation of Vitamins C and E may protect against vascular dementia and may improve cognitive function in later life.

However, Drachman et al11 argues that the treatment does not improve scores on the Mini-Mental State Examination on the cognitive function of the AD assessment scale. This raises the possibility that the treatment had only symptomatic effects and did not alter the progression of the disease. Buckholtz12 comments that the study reinforced the thinking that Vitamin E as an antioxidant plays a treatment role in AD. He suggests further research to determine whether Vitamin E can actually delay the development of symptoms in early course of the disease.

Should antioxidant vitamins be recommended?

Antioxidant vitamins seem to be useful in preventing and treating dementia. Is supplementing the diet with antioxidant vitamins useful?

Eighty-one elderly hospitalised subjects were recruited for a double-blind placebo controlled study to examine the effect of low dose supplement of antioxidant vitamins and minerals on biological and functional parameters of free radical and metabolism.13 Subjects were randomly assigned to one of the four groups: placebo group, mineral group (20 mg zinc and 100 μg selenium), vitamin group (120mg Vitamin C, 6 mg β-carotene and 15 mg Vitamin E), mineral and vitamin group (mineral plus vitamin). A large frequency of Vitamin C, zinc and selenium deficiencies was observed as baseline. After 6 months, a significant increase in vitamin and mineral serum levels was observed in the treatment groups. The increase ranged from 1.1 - 4.0 fold depending on the nutrients. Girodom et al concludes that antioxidant defence in elderly subjects was improved with low dose Vitamin C, Vitamin E and β-carotene supplements. To prevent vitamin deficiency and increase antioxidant intake, supplementation may be necessary.14,15 Many elderly are prone to vitamin deficiency. The diet imbalance may be due to chewing problem, taste, poor appetite and other age-related medical conditions.

Dosage of Vitamin E

Some human clinical trials have involved very high doses of Vitamin E. In DATATOP study, the subjects had been taking Vitamin E 2000 iμ daily for 37 to 644 days.16 The net increase in spinal fluid α-tocopherol concentration showed a significant positive linear correlation with the number of days of Vitamin E ingestion. The α-tocopherol concentration within spinal fluid had not reached the highest value even after 644 days of treatment. The observation suggests that long-term treatment with Vitamin E would tend to increase Vitamin E concentration within the brain and may increase the effectiveness of Vitamin E as an antioxidant in neurological degenerative disease. Piptock17 reviewed 10 clinical studies and concludes that ingestion of Vitamin E at dosages of 100-3,200 iμ/d from periods of 4 weeks to a few months was not associated with any adverse effect. The study of Sano et al 9 confirms this observation. These reports indicate that Vitamin E can be used by human in fairly large doses. However, data on the effects of pharmacological doses of Vitamin E in human over very long periods are still not available. Adverse reactions from consumption of high dose Vitamin E have been reported mainly in subjects with suboptimal Vitamin K status. Piptock proposes that Vitamin E quinone – an oxidation product of Vitamin E – interferes with the carboxylase reaction that uses Vitamin K as a cofactor and converts several of the coagulation factors to their active forms. These changes are reversed readily by administration of Vitamin K. Therefore, it would be prudent to monitor coagulation function in persons with potential Vitamin K deficiency, or persons undergoing anti-coagulant therapy.

Ginkgo biloba and dementia

Ginkgo Biloba Extract (GBE) is among the leading prescription medicines in Germany and France and it is one of the most popular herbs sold in US. For herbal purposes, the Ginkgo leaves are used in the form of a concentrated, standard extract. GBE has been used for treating memory impairment, concentration difficulties, tinnitus, headache, dementia, asthma, and hypovolaemic shock.18,19 The most important antioxidant ingredients in GBE are: flavonoids that prevent cell damage, terpenoids that reduces blood clots by reducing the platelet aggregation. GBE promotes vasodilatation and improves blood flow in the arteries and capillaries.20 The above explain why GBE is used to treat dementia.

Kleizen and Knipschild20 reviewed 40 trials on ginkgo and cerebral insufficiency. The methodological quality of all the 40 trials has met the predefined criteria of good methodology. All trials reported positive results. In most trials the dosage was 120 mg GBE a day, given for at least 4-6 weeks. A number of clinical researches also supported the effective treatment role of GBE in dementia.

A 52 weeks randomised double-blind, placebo controlled, parallel group, multi-centre study recruited subjects with mild to severe AD or multi-infarct dementia.18 Patients were assigned randomly to treatment with GBE (120 mg/d) or placebo. AD Assessment Scale – Cognitive substance (ADAS-Cog), Geriatric Evaluation by Relatives Rating treatment (GERRI) and Clinical Global Impression of Change (CGIC) were used as outcome measures. The study concludes that GBE is safe and appears capable of stabilising and improving the cognitive performance and social functioning of demented patient for 6 months to 1 year.

Kanowski et al21 recruited 156 out-patients suffering from mild to moderate degenerative dementia of the Alzheimer type or Multi-infarct dementia. 78 patients were on placebo and 78 patients were on GBE 120 mg twice a day. After 24 weeks, a significant improvement was shown in cognitive function as measured with a variety of standardised tests.

Another interesting study gave a single dose of 20 mg or 600 mg GBE to 18 elderly patients with memory impairment.22 After one hour, the speed of information processing assessed by the Dual Coding test improved significantly.

A double-blind, placebo controlled trial involved 27 elderly patients with mild to moderate memory impairment. 40 mg GBE was given 3 times daily for 24 weeks. An improvement was found in the Digit Copying test of Kendrick Battery compared with placebo.23

Dosage of GBE

From the above-cited papers, a typical recommended dosage of GBE is 40-60 mg twice to three times daily. However, a high daily dosage of 120 to 260 mg is commonly used in the clinical trials. Duration of therapy is not defined clearly but typically extends from 6 to 8 weeks. Side effects associated with ingestion of GBE are relatively mild and usually include headache, GI upset and dizziness. Large doses may cause restlessness, nausea, vomiting and diarrhoea. In addition, about 6% of the ginkgo users reported minor side effects such as allergic skin reaction, headache and stomach upset. GBE reduces clotting time of blood; this is of concern in those elderly taking anti-coagulants.19,22

Doraisamy24 cited some unpublished data and suggested a combination therapy of cholinesterase inhibitors and Vitamin E, seligeline, or ginkgo biloba in early AD. At an interactive symposium on AD held during 1997 American Psychiatric Association Annual Meeting in response to a hypothetical scenario, the majority of participants (78% of 316) agreed that they would consider recommending a quadruple drug regimen – that is cholinesterase inhibitor, Vitamin E, oestrogen, indomethacin – if their mothers had AD.

Antioxidant and PD

The Rotterdam Study25 was a large community-based study on PD. All participants of the study were individually screened for PD. Besides the researcher-administered semiquantitative food frequency questionnaire, the participants were asked whether they consumed vitamin supplement. It showed that individuals with higher Vitamin E intake were significantly less often to have PD than those with low Vitamin E intake. Intake of β-carotene was also related to PD but the correlation was not significant. Vitamin C and diet flavonoids intake showed no effect on PD. The Rotterdam study concluded that a high intake of dietary Vitamin E might protect against the occurrence of PD.

Another population based, case control study examined the dietary intake of antioxidants and other oxidative compounds associated with PD.26 Dietary intake was assessed by a semi-quantitative food frequency questionnaire in 110 PD patients and 287 control subjects. A higher fats intake was observed in patients with PD which supported the hypothesis that oxidative stress and lipid peroxidation were important in the pathogenesis of the disease. No significant difference was observed with vitamin and antioxidant activity from food or supplement.

DATATOP was a double-blind, placebo controlled study using 2,000 iμ Vitamin E daily or 10 mg seligiline daily or both for PD patients.16 The results did not support the use of Vitamin E.

From the above findings, it may be postulated that Vitamin E may not help in treating PD but diet rich in Vitamin E may prevent the disease.

Antioxidant and CHD

Antioxidants are proposed to inhibit multiple proatherogenic and prothrombotic oxidative events in the artery wall.27,28 Therefore, diet rich in antioxidants may protect against CHD.

In England and Scotland, it is well known that the consumption of fresh fruits and green vegetables is inversely related to mortality from cerebrovascular disease. Also, the calculated Vitamin C intake is inversely related to standardised mortality rates for coronary heart disease.

Vitamin E and CHD

Stamfter29 analysed the data from over 85,000 nurses who participated in a health study. Risk of major coronary disease was lowest in women with the highest dietary Vitamin E intake. Lower risk was associated with level of Vitamin E intake that was achievable by the supplementation of Vitamin E. Subsequent analysis revealed a 43% lower risk of Vitamin E supplement users versus non-users and an inverse relationship between risk and duration of supplement use. A similar benefit for Vitamin E rich diet was reported in a Health Professional Follow-up study. Diets rich in Vitamin E protect against CHD.30

The cohort study of Gillman et al supports the benefit of fruits and vegetables in stroke prevention.31 They conducted a population-based longitudinal study, which recruited 328 men, aged 45-65, who were free of CHD at baseline. The diet of each subject was assessed at baseline by a single 24-hour recall. The mean number of fruits and vegetables serving per day was 5.1 (± 2.8). From the twentyyear follow up, it concludes that intake of fruits and vegetables may protect against stroke development in man.

The Cambridge Heart Antioxidant study tested the effect of 400 or 800 iμ of tocopherol daily on subsequent cardiovascular events in patients with angiographic evidence of coronary atherosclerosis.32 Risk of myocardial infarction (MI) and all cardiovascular events were reduced. The 800 iμ treatment group had an average 200 days delay for fatal cardiovascular end points.

Rapolar et al found the risk of subsequent non-fatal MI was reduced by 58% in the group treated by tocopherol, but it did not reduce the risk of fatal coronary event.33

However, in The Heart Outcomes Prevention Evaluation Study a different result was generated. The study enrolled a total of 2,545 women and 6,996 men, who were at least 55 years old and at high risk of cardiovascular events.34 These patients were randomly assigned according to a two by two factorial design to receive either 400 iμ of Vitamin E daily from natural sources or matching placebo and either an angiotensin converting enzyme inhibitor ramipril or placebo for a mean of 4.5 years. There was no significant difference between Vitamin E and placebo group and there was no adverse effect found of Vitamin E. It concluded that the reason for the above result might be the use of Vitamin E alone without other antioxidants.

An association between higher Vitamin E intake and lower rates of CHD was established in the above epidemiological studies but was not definite in the clinical trials. It has been noted that most of the epidemiological studies are on dietary Vitamin E that is taken with a lot of other antioxidants and micro-nutrients. It is possible that Vitamin E supplement requires other antioxidants or micronutrients as cofactors to produce the beneficial effects.

β-carotene and CHD

Many epidemiological studies show diet rich in β-carotene is inversely associated with CHD risk.35-37 Other clinical trials have shown no effect of β-carotene supplementation.37,38

Further research to understand the interaction of other carotenoids that coexist with β-carotene in the diet, or other plant-derived compounds with β-carotene may explain the discrepancies between the epidemiological and clinical findings.

Flavonoids and CHD

Most of the epidemiological data on relationship of flavonoids and cardiovascular disease has emerged post COMA 1994.39 Flavonoids present in red wine have been suggested as an explanation for the low CHD rate in French who are red wine drinkers. The phenomenon is known as "French Paradox". Flavonoids are a complex family of compound with approximately 4,000 types categorised into different subgroups. Flavonoids are powerful antioxidants found in many fruit and vegetable (and their juice) and red wine. Tea is a particularly rich source of flavonoids. The average intake of all flavonoids is about 1 g per day in every English. Each ordinary cup of tea contains about 2,000 mg flavonoids. Flavonoids are able to moderate enzyme activity, protect LDL cholesterol from oxidation, inhibit platelet aggregation and have potent antioxidant activity.40 A protective effect of flavonoids on CHD was concluded in many studies.41-44 Other studies showed definite link between tea drinking and the reduction in CHD mortality.45,46 In a Norwegian study,46 the risk of dying from CHD was 36% lower for men with daily consumption of at least 1 cup of tea compared with men drinking less or none. It would be sensible to increase flavonoids rich food and drink to protect against CHD.

Antioxidant and cancer

Again epidemiological evidence suggested antioxidants protect against cancer, but clinical trails did not.47-50 Block51 reviewed studies about fruits and vegetables on cancer protection. 128 out of 156 dietary studies revealed statistically significant protection effect of fruits and vegetables consumption on cancer. For most cancer sites, persons with low fruits and vegetables intake experience about twice the risk of cancer compared with those with high intake. The cancer sites include the non-intestinal area such as lung, larynx, bladder, cervix, ovary, endometrium and breast. Evidences in protection for intestinal tract, such as oral cavity, pancreas, stomach and colorectal are even stronger. Kristi et al52 also does a similar review that summarised 200 human epidemiological studies and 22 animal studies. The epidemiological studies consistently support that vegetable and fruit consumption is inversely related to cancer occurrence.

Many clinical studies have used the well known antioxidants, such as Vitamins A, C and E found in fruits and vegetables to test the effect on cancer. However, the findings are different. Omenn et al53 conducted a multi-centre, randomised, double-blind, placebo controlled primary prevention trial to investigate the effects of a combination of 30 mg of β-carotene per day and 25,000 iμ of retinol (Vitamin A) per day. There was no significant difference in the active treatment group and placebo group. Greenbery48 conducted a clinical trial of antioxidant vitamin on prevention of colorectal adenoma. It shows no evidence that either β-carotene or Vitamins C and E reduce the incidence of adenomas.

Therefore, supplementation of antioxidants vitamins seems to have no protective role against cancer, but diets high in fruits and vegetables, which is rich in antioxidants have a definite protective role.

Increase consumption of fruits and vegetables

There is strong epidemiological evidence on the protection role of fruits and vegetables in CHD and cancer, but clinical trials using supplementation of antioxidants vitamins did not show the same result. Therefore, are we missing something important in the clinical trials? Other dietary factors may have more important contributions to the reduction in the risk of CHD and cancer associated with a high vegetables and fruits intake. There are lots of other substances in fruits and vegetables that may protect us against some diseases. Please refer to Table 2 for these substances in fruits and vegetables. Supplementation of vitamins or minerals may not be beneficial to our health as there are still many substances in fruits and vegetables which are not known and researchers have not elicited how the known substances work. Vitamins A, C and E are only the "tip of the iceberg" of the substances in fruits and vegetables. One definitely known fact is that increased intake of fruits and vegetables has a preventive role in CHD and cancer, and may be in dementia. Fruits and vegetables are definitely good to our health. Therefore, it is sensible to advice the public to increase consumption of fruits and vegetables. In the UK, the government has put a lot of efforts in promoting the consumption of five portions of fruits and vegetables a day. Please refer to Table 3 for the portion size of fruits and vegetable. There are some practical tips for increasing the fruits and vegetables consumption, please refer to Table 4 for details.

Conclusion

Antioxidant is not the solution to all diseases but it does help in some aspects of different diseases. Clinical evidence has shown the possible benefits of Vitamin E in the treatment of dementia. The use of GBE is still controversial. Further research is needed. More investigations on different antioxidant substances in fruits and vegetables are also needed. We need to increase the consumption of fruits and vegetables in order to increase the ingestion of antioxidants and other protective substances.

Key messages

  1. Clinical evidence has shown the possible benefits of Vitamin E in treatment of dementia while the use of ginkgo biloba is still controversial.
  2. Epidemiological evidence has shown the protective role of antioxidants in coronary heart disease and cancer, but clinical trials did not. Some other substances in fruits and vegetables might play a more important role.
  3. More investigations on different antioxidant substances in fruits and vegetables are needed.
  4. It might be beneficial to advise the public to increase the consumption of fruits and vegetables.

V S F Chow,
State Registered Dietitian (U.K.),
Dietetics Department, United Christian Hospital.

Correspondence to : Ms V S F Chow, Dietetics Department, United Christian Hospital, Kwun Tong, Kowloon, Hong Kong.

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