B VITAMIN SUPPLEMENTS AND PROGRESSION OF COGNITIVE DECLINE IN ALZHEIMER DISEASE
Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ; for the Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300:1774–1783.
Considerable evidence links high levels of homocysteine with vascular disease, vascular dementia and Alzheimer's disease, and cognitive decline. It has been proposed that reduction of circulating levels of homocysteine could be of therapeutic benefit in preventing vascular impairment and cognitive decline. The B vitamins B12 and folic acid are important in the remethylation of homocysteine into methionine, and vitamin B6 plays a role in the transsulfuration of homocysteine into cysteine, with a net decrease in homocysteine levels. B vitamin supplementation is effective in reducing homocysteine in both adequately nourished and in B vitamin-deficient populations; however, the use of B vitamins to reverse or offset vascular disease has been generally disappointing. Aisen et al. report on a multicenter, placebo-controlled randomized trial investigating the ability of B vitamin supplementation to slow the progression of cognitive decline in mild to moderate Alzheimer's disease.
Individuals with normal B vitamin status and probable Alzheimer's disease, defined here as a Mini-Mental State Examination (MMSE) score between 14 and 26 (a lower number indicates greater impairment), were randomized into vitamin supplementation (n = 240) or placebo (n = 166) and followed for up to 18 months. Vitamin supplements consisted of 5 mg/d folic acid, 1 mg/d vitamin B12, and 25 mg/d vitamin B6. The primary cognitive outcome measure was a targeted 25% reduction in scores on the Alzheimer Disease Assessment Scale (ADAS-cog), with additional outcomes including MMSE scores, Clinical Dementia Ratings, and the Alzheimer Disease Cooperative Study activities of daily living scale (ADCS-ADL). Plasma homocysteine and B vitamin levels were determined at baseline and 6, 12, and 18 months after initiating treatment, and cognitive assessments were conducted at baseline and every 3 months after initiating treatment. Homocysteine levels at the beginning of the study were not overly elevated in either condition (∼9.16 umol/L) and were significantly reduced in the vitamin supplementation condition relative to placebo at 6 months after initiating treatment and throughout the remainder of the study. Cognitive assessments did not differ at any time point over the test period between the supplemented group and placebo condition. There were a significantly greater number of adverse events related to self-disclosure of depression in the supplemented group relative to placebo, but these were not related to significantly different scores on depression subscales on a neuropsychiatric inventory and were not reflected in differences in initiation of antidepressant treatment. The authors conclude that under the present conditions, there is no compelling evidence to support the use of B vitamin supplementation in the prevention of cognitive decline in Alzheimer's disease.
Comment: Drs. Clarke and Bennett expand further on the proposed relationship between homocysteine levels and vascular pathology and cognitive impairment. Although data from the FACIT trial show that older individuals supplemented with folic acid for 3 years show improvements in cognitive performance, intervention trials have, in general, shown little benefit of vitamin supplementation on brain function. Importantly, the commentators suggest that existing cognitive impairment may not be treatable with nutritional intervention, and that any intervention with folic acid would be complicated in areas with mandatory folic acid fortification. While not discouraging further avenues of research, the accumulated data at present suggest little benefit in routinely prescribing vitamin supplements to prevent cognitive decline in individuals with normal vitamin status.
Comment: Clarke RJ, Bennett DA. B vitamins for prevention of cognitive decline: insufficient evidence to justify treatment. JAMA. 2008;300:1819–1821.
VITAMIN D AND COLORECTAL CANCER RISK
Mizoue T, Kimura Y, Toyomura K, Nagano J, Kono S, Mibu R, Tanaka M, Kakeji Y, Maehara Y, Okamura T, Ikejiri K, Futami K, Yasunami Y, Maekawa T, Takenaka K, Ichimiya H, Imaizumi N. Calcium, dairy foods, vitamin D, and colorectal cancer risk: The Fukuoka colorectal cancer study. Cancer Epidemiol Biomarkers Prev. 2008;17:2800–2807.
The role of vitamin D and calcium in reducing risk for colorectal cancer is established in the epidemiological literature, but the nature of the relationship remains unclear. In western populations, calcium in combination with vitamin D may have anticancer effects in the colon, and supplementation with calcium may have protective effects only among individuals with higher levels of vitamin D. In Asian populations, where calcium intake is low, research is limited on the impact of these nutrients on colorectal cancer risk. In the present study, Mizoue et al. examine the interaction of vitamin D and calcium intakes on colorectal cancer risk in a Japanese population consuming a diet high in vitamin D but low in calcium.
Eight hundred and thirty-six patients (40% women) with confirmed colorectal adenomas were matched with 831 controls (38% women). Dietary intakes for the previous year were estimated using a computer-based interview corresponding with data collected using food frequency questionnaires. Data were validated against 7-day food intake diaries taken during the four seasons. In addition to dietary vitamin D, a proxy of sunlight exposure was obtained through surveys of outdoor work and leisure activities, but serum levels of 25-OH vitamin D were not determined. Estimated intakes of vitamin D and calcium were stratified into quintiles, and odds ratios of colorectal cancer were generated. In comparison with controls, individuals with colorectal cancer consumed smaller amounts of calcium and were more likely to be obese. In individuals with low sunlight exposure, there was an inverse relationship between vitamin D intake and incidence of cancer. Odds ratio for cancer risk decreased in individuals drinking more milk, and in those consuming more calcium. Higher intakes of calcium were associated with decreased risk for colorectal cancer in individuals with the highest levels of vitamin D intake, but this association was not seen in individuals with lower levels of vitamin D intake. This study would have been strengthened by inclusion of serum levels of 25-OH vitamin D, particularly as both the outdoor activity survey and estimates of vitamin D intake were low. As a result, the influence of vitamin D on colorectal cancer risk may have been underestimated. Among the Japanese, in whom calcium intake is low, initiatives to increase calcium intake while maintaining present high levels of vitamin D may be effective in reducing risk for colorectal cancer.
RELATIONSHIP BETWEEN SOY INTAKE AND SPERM CONCENTRATION
Chavarro JE, Toth TL, Sadio SM, Hauser R. Soy food and isoflavone intake in relation to semen quality parameters among men from an infertility clinic. Hum Reprod. 2008;doi:10.1093/humrep/den243.
Soy and soy-based foods are dietary sources of isoflavones, which have estrogen-like effects at estrogen receptors. Animal studies indicate that exposure to phytoestrogens during development results in impaired development of male reproductive organs. Although it is proposed that exposure to soy foods may affect male fertility, research in human males remains limited. The present study led by Chavarro et al. investigates the relationship between intake of soy foods and a number of semen quality parameters in men seeking evaluation at an infertility clinic.
Semen samples were collected from 99 men and were analyzed for sperm morphology, motility, and concentration. Soy intakes were determined using a limited food frequency questionnaire that quantified the amounts of 15 different soy foods. The specific isoflavones daidzien, genistein, and glyciten were derived from food frequency estimates using the USDA food database. Soy intakes were categorized into “no soy” and three tertiles of intake. Intakes of soy and soy isoflavones were inversely related to sperm concentration. When adjusted for covariates including BMI, age, alcohol intake, and smoking, men who were in the highest tertile for soy intake had significantly lower concentrations (41 million fewer sperm/ml) than men who did not consume soy. When individual isoflavones were examined, the inverse relationship was similar but did not reach significance. Other measures of semen quality, including total sperm count, sperm motility, and sperm morphology, were not related to soy intake. The relationship between soy intakes and sperm concentration was stronger in overweight or obese men and in men in the highest percentile of sperm concentration. The clinical impact of this relationship remains unknown. The authors acknowledge the limitations of this study, including the cross-sectional design. However, this study is, at present, the largest to investigate the impact of soy food consumption on semen quality, and the authors urge more rigorous investigation on this underinvestigated topic.
SHORT-TERM CALORIE RESTRICTION AND BONE HEALTH
Redman LM, Rood J, Anton SD, Champagne C, Smith SR, Ravussin E; Pennington Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) Research Team. Calorie restriction and bone health in young, overweight individuals. Arch Intern Med. 2008;168:1859–1866.
Calorie restriction (CR), a reduced calorie but nutritionally replete diet, may decrease the rate of aging and increase life span. With CR, individuals lose weight (both fat and lean mass), and show reduced insulin concentrations and metabolic rate. Of concern to those consuming restricted calorie diets, reductions in energy intake in overweight or obese people can result in loss of bone mass. Therefore, any bone loss seen with CR could potentially offset any benefits of following a CR regime. In the present report, Redman et al. investigate the effects of 6 months of CR, both with and without aerobic activity, on markers of bone health in adults.
Forty-six men and women (BMI between 25 and 30) were randomized into one of four conditions for 24 weeks. The control condition followed a healthy weight maintenance diet. The remaining three groups followed one of three caloric restriction conditions: 25% calorie restriction from baseline intake (CR); 12.5% reduction in caloric intake along with 12.5% increase in energy output through aerobic exercise (CR + EX); and a very low-calorie diet (890 kcal/d) designed to result in 15% weight loss (LCD). Diets were based on the American Heart Association guidelines and met the RDI for all vitamins and minerals. Participants were instructed to not use additional micronutrient supplementation, including calcium. Study outcome measures for bone health included bone mineral density and serum bone markers. Data were collected on bone measures at baseline and at 6 months. Participants in all reduced calorie conditions lost weight (∼10–13%). No changes were seen in bone mineral density between controls and calorie-restricted conditions. Bone resorption was increased in the calorie-restricted groups relative to control, and markers of bone formation were decreased in the CR group relative to baseline. Although there were changes in serum bone markers with calorie restriction, the authors maintain that there is minimal impact on bone health following 6 months of calorie restriction with adequate calcium intake in adults.
ASSOCIATIONS AMONG CORONARY HEALTH, DEPRESSION, AND OMEGA-3 FATTY ACID LEVELS
Amin AA, Menon RA, Reid KJ, Harris WS, Spertus JA. Acute coronary syndrome patients with depression have low blood cell membrane omega-3 fatty acid levels. Psychosom Med. 2008;doi:10.1097/PSY.0b013e318188a01e
Depression is frequently seen concurrently with a myriad of health problems, including cardiac patients, and is a predictor of adverse outcomes. Depression in individuals with acute coronary syndrome (ACS) is associated with increased risk of cardiovascular events, healthcare utilization, and death. The underlying tenet of the present report by Amin et al. is the conjecture that depression and coronary artery disease share a common causal factor.
Considerable research shows dietary intake of omega-3 fatty acids is protective in vascular health. Other research indicates that intake of omega-3 fatty acids is associated with lower rates of depression, and may be useful in the management of depression, although findings on this subject are mixed. The present data represent a cross-sectional analysis comparing depressive symptoms and blood cell membrane omega-3 fatty acid (DHA + EPA) composition in 759 patients with ACS (67% male). Depressive symptoms were quantified using the Patient Health Questionnaire-9 (PHQ). Total scores range from 0 to 27 with higher scores indicating greater depressive symptomology. Participants were dichotomized into depressed (PHQ ≥ 10) and not depressed (PHQ < 10). Blood cell membrane EPA and DHA levels were inversely related to the presence of depressive symptoms. Patients with depression had lower levels of DHA and total omega-3 fatty acid levels relative to patients without depression. After adjusting for other factors, higher levels of omega-3 fatty acids were independently associated with reduced depressive symptoms in ACS patients. By using membrane levels of omega-3 fatty acids, the investigators provide a more stable measure of fatty acid status, and the data provide a more accurate long-term estimate of fatty acid levels in comparison to data obtained from plasma levels of omega-3 fatty acids. The present study does not and cannot answer the initial question of whether depression and ACS share a common substrate. However, this study does lend credence to the proposal that increasing omega-3 fatty acid profiles may be of utility in management of depression in ACS.
IMPACT OF LOW-DOSE PHYLLOQUINONE SUPPLEMENTATION ON BLOOD LIPIDS
Kristensen M, Kudsk J, Bügel S. Six weeks phylloquinone supplementation produces undesirable effects on blood lipids with no changes in inflammatory and fibrinolytic markers in postmenopausal women. Eur J Nutr. 2008;47:375–379.
In the November 2008 Nutrition Updates, we discussed research evaluating the beneficial effects of menaquinone (vitamin K2) in offsetting coronary calcification in post-menopausal women. Intake of phylloquinone (vitamin K1) did not confer any benefit in coronary calcification. The active forms of vitamin K, menaquinone and phylloquinone, may play different roles in cardiovascular health, and these differences may explain discrepancies in the literature on vitamin K intake and cardiovascular disease. Kristensen et al. describe the effects of short-term, relatively low-dose supplementation phylloquinone on blood lipids, inflammatory markers, and coagulation factors in post-menopausal women.
It was proposed that 500 ug phylloquinone supplementation for 6 weeks would have cardioprotective effects in these women. Thirty-one women were assigned to groups within a randomized, crossover, placebo-controlled design. Participants received three 6-week sessions (control, 200 µg phylloquinone; 500 µg phylloquinone) with wash-out periods of 3 weeks between sessions. This study was originally designed to study the effects of phylloquinone on bone metabolism, and data from the 200 µg phylloquinone session are not reported. Cardiovascular outcome measures included total serum cholesterol, LDL and HDL, and triglycerides. Inflammatory and coagulation factors were also measured. Relative to placebo, 6-week supplementation with 500 µg phylloquinone produced a significant 15% increase in triglycerides and trend for HDL cholesterol to decrease. Other blood measures were unaffected by phylloquinone supplementation. Under the described conditions, phylloquinone failed to show anti-inflammatory properties and had an unfavorable impact on triglycerides and, to a lesser degree, HDL cholesterol. Although the authors suggest that higher doses or longer-term supplementation of phylloquinone might be required to see a positive effect of vitamin K supplementation on cardiovascular risk factors, the rationale for this recommendation is unclear. If data had been presented for the 200 µg phylloquinone group, with similar negative effects on blood markers, then the argument for an inverse dose-response effect of phylloquinone would be strengthened. The present data do not support the proposal that supplementation with phylloquinone has cardioprotective effects.