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Folate Benefits Clinical Studies

  1. Short-Term Folate, Vitamin B-12 or Vitamin B-6 Supplementation Slightly Affects Memory Performance But Not Mood in Women of Various Ages.

    Bryan J, Calvaresi E and Hughes D.
    J. Nutr. 2002;132:1345-1356.

    Based on research demonstrating associations between folate, B-12 and B-6 vitamins and cognition and mood, we investigated the effects of short-term supplementation in 211 healthy younger, middle-aged and older women who took either 750 µg of folate, 15 µg of vitamin B-12, 75 mg of vitamin B-6 or a placebo daily for 35 d. In addition, we examined associations between dietary intake of these vitamins and cognition and mood. Usual dietary intake status was estimated using a retrospective, self-report, quantified food frequency questionnaire. Participants completed alternate forms of standardized tests of cognitive processing resources, memory, executive function, verbal ability and self-report mood measures before and after supplementation. Supplementation had a significant positive effect on some measures of memory performance only, and no effect on mood. Dietary intake status was associated with speed of processing, recall and recognition and verbal ability.

  2. Folate deficiency in elderly subjects: value of folate supplementation in the management of behavior disorders. (In French)

    Brocker P, Lebel C, Maurin H, Lods JC.
    Sem Hôp Paris. 1986;62(27):2135-2139.

    Seventy-five percent of 1000 hospitalized elderly subjects were considered as having folate deficiency (serum folate concentration assayed using lactobacillus caseï under 5ng/ml in 750 patients). Macrocytic anemia, found in only 45 patients (6%) proved valueless for the detection of folate deficiency in elderly patients. Fifty randomly selected, folate-deficient patients with behavior disorders were given 50 mg folinic acid parenterally after an initial 21-day treat-free observation period. Pre and post treatment scores were determined using two different scales (Nosie and Hamilton). A significant (p<0.001) improvement in cerebral function was found: 4 patients with depression and 3 with dementia recovered complete self-sufficiency. The action of folinic acid in conduct disturbances in elderly subjects is discussed. Folinic acid plays a part in the synthesis of neurotransmittors (noradrenaline, dopamine, serotonine) and S-adenosylmethione that are thought to be involved in the mechanism of depression and dementia in elderly subjects. The authors underscore the need for detection of folate deficiency whenever possible or routine administration of supplemental folate.

  3. Reduced risk of Alzheimer's disease with high folate intake: The Baltimore Longitudinal Study of Aging.

    Corrada M, Kawas C, Halldrisch J, Muller D, Brookmeyer R.
    Alzheimer's & Dementia. 2005;1:11-18.

    Study findings have suggested an association between Alzheimer's disease (AD) risk and several vitamins and have speculated about their use as preventive agents. Here, we examine whether total intake (intake from diet plus supplements) of antioxidant vitamins (E, C, carotenoids) and B vitamins (folate, B6, and B12) is associated with a reduced risk of AD. Methods: Participants were 579 nondemented elderly volunteers from the Baltimore Longitudinal Study of Aging who completed dietary diaries and recorded supplement intake for a 7-day period. Cox regression was used to estimate the relative risk (RR) of AD associated with total vitamin intake categorized into levels above or below the Recommended Dietary Allowance (RDA). Results: After a mean follow-up of 9.3 years, AD developed in 57 participants. Higher intake of folate (RR, 0.41; 95% confidence interval [CI], 0.22 to 0.76), vitamin E (RR, 0.56; 95% CI, 0.30 to 1.06), and vitamin B6 (RR, 0.41; 95% CI, 0.20 to 0.84) were associated individually with a decreased risk of AD after adjusting for age, gender, education, and caloric intake. When these 3 vitamins were analyzed together, only total intake of folate at or above the RDA (RR, 0.45; 95% CI, 0.21 to 0.97) was associated with a significant decreased risk of AD. No association was found between total intake of vitamins C, carotenoids or vitamin B12 and risk of AD. Conclusions: These findings suggest that a total intake of folate at or above the RDA is associated with a reduced risk of AD. Additional studies are necessary to further investigate whether folate or other(s) unmeasured factor(s) may be responsible for this reduction in risk.

  4. Effects of 3-year Folic Acid Supplementation on Cognitive Function in Older Adults in the FACIT trial: A randomized, double-blind, controlled trial.

    Durga J, van Boxtel PJ, Schouten EG, Kok FJ, Jolles J, Katan MB, Verhoef P.
    The Lancet. 2007;369:208-215.

    Change in cognitive function attributed to folate

    Background: Historic reports on the treatment of pernicious anemia with folic acid suggest that high-level folic acid fortification delays the diagnosis of or exacerbates the effects of vitamin B-12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive. Furthermore, experimental investigation is unethical. Objective: We examined the relations between serum folate and vitamin B-12 status relative to anemia, macrocytosis, and cognitive impairment (i.e., Digit Symbol-Coding score _34) in senior participants in the 1999-2002 US National Health and Nutrition Examination Survey. Design: The subjects had normal serum creatinine concentrations and reported no history of stroke, alcoholism, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries (n_1459). We defined low vitamin B-12 status as a serum vitamin B-12 concentration _148 pmol/L or a serum methylmalonic acid concentration _210 nmol/L-the maximum of the reference range for serum vitamin B-12-replete participants with normal creatinine. Results: After control for demographic characteristics, cancer, smoking, alcohol intake, serum ferritin, and serum creatinine, low versus normal vitamin B-12 status was associated with anemia [odds ratio (OR): 2.7; 95% CI: 1.7, 4.2], macrocytosis (OR: 1.8; 95% CI: 1.01, 3.3), and cognitive impairment (OR: 2.5; 95% CI: 1.6, 3.8). In the group with a low vitamin B-12 status, serum folate _59 nmol/L (80th percentile), as opposed to _59 nmol/L, was associated with anemia (OR: 3.1; 95% CI: 1.5, 6.6) and cognitive impairment (OR: 2.6; 95% CI: 1.1, 6.1). In the normal vitamin B-12 group, ORs relating high versus normal serum folate to these outcomes were _1.0 (Pinteraction _ 0.05), but significantly _1.0 only for cognitive impairment (0.4; 95% CI: 0.2, 0.9). Conclusion: In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B-12 status was normal, however, high serum folate was associated with protection against cognitive impairment.

  5. Low folate levels in the cognitive decline of elderly patients and the efficacy of folate as a treatment for improving memory deficits.

    Fioravanti M, Ferrario E, Massaia M, Cappa G, Rivolta G, Grossi E and Buckley AE.
    Arch Gerontol Geriatr. 1997;26:1-13.

    The relevance of low folate levels as determinants of cognitive deficits and the usefulness of folate supplementation in the treatment of cognitive deficits was reviewed from the literature. Over 40 papers and book chapters published in English, French, German, Italian and Spanish were examined. This represents those papers published in the international literature in the last 10 years which were identified by various key words including folate cognition and aging (or aging). Among these papers, only 13 articles specifically addressed issues relevant to the criteria adopted for this review. The remaining papers were principally concerned with depression and or with other pathologies of the aged associated with folate deficiency. Although the specific role of low folate levels in the physiopathology of dementia is still under debate, a growing consensus is emerging in the literature were low folate as well as cobalamin levels in aged patients with cognitive deficits are being considered as a sign of functional problems in the absorption and utilization of vitamins and not merely as a sign of bad eating habits. In studies where folate compounds were evaluated for treatment effects, the results of a majority of investigations indicated that folate treatment was effective in lessening cognitive deficits. Treatment efficacy, however, has not yet been sufficiently demonstrated by these results because there were no controlled studies and the methodology was heterogeneous for the evaluation of cognitive characteristics. An ad hoc double-blind, controlled versus placebo pilot study was undertaken to evaluate the efficacy of folic acid in 20 aged patients with abnormal cognitive decline and folate level below 3 ng/ml to better understand the value of this type of intervention. Our results from this preliminary study demonstrated that patients treated with folic acid for 60 days showed a significant improvement on both memory and attention efficiency when compared with a placebo group. The intensity of memory improvement was positively correlated with initial severity of folate deficiency. On the contrary, the severity of initial cognitive decline was unrelated to the degree of folate deficiency.

    ® 1997 Elsevier Science Ireland Ltd

  6. Vitamin B12-B6-Folate treatment improves Blood-Brain Barrier function in patients with Hyperhomocysteinaemia and Mild Cognitive Impairment

    Lehmann M, Regland B, Blennow K, and Gottfries CG.
    Dementia and Geriatric Cognitive Disorders 2003;16:145-150.

    Thirty patients had mild cognitive impairment and increased homocysteine levels in serum. On average, they were supplemented orally with a high dose of a vitamin B12-B6-folate combination for 270 days. All patients had normal serum B12 and folate levels at baseline. Cerebrospinal fluid levels of the tau protein (CSF-tau) and the albumin ratio were measured before and after treatment. The serum homocysteine levels were normalised [sic] after treatment. The albumin ratio significantly correlated with vascular risk factors. At baseline, the ratio was higher in the patients in comparison with age-matched controls. After treatment, the ratio was significantly reduced, which may indicate a tightening of the blood-brain barrier. The CSF-tau levels did not change significantly although there was a numeric decline. None of the patients progressed into dementia during the treatment period. When treated with a vitamin B12-B6-folate combination, patients with mild cognitive impairment and hyperhomocysteinaemia [sic] appear to improve their blood-brain barrier function. They may also stabilise their cognitive status. Further investigations are warranted on the role of blood-brain barrier dysfunction in the pathogenesis of dementia.

  7. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification.

    Morris MS, Jacques PF, Rosenberg IH, Selhub J.
    Am J Clin Nutr. 2007;85:193-200.

    Background: Historic reports on the treatment of pernicious anemia with folic acid suggest that high-level folic acid fortification delays the diagnosis of or exacerbates the effects of vitamin B-12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive. Furthermore, experimental investigation is unethical.

    Objective: We examined the relations between serum folate and vitamin B-12 status relative to anemia, macrocytosis, and cognitive impairment (ie, Digit Symbol-Coding score <34) in senior participants in the 1999-2002 US National Health and Nutrition Examination Survey.

    Design: The subjects had normal serum creatinine concentrations and reported no history of stroke, alcoholism, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries (n = 1459). We defined low vitamin B-12 status as a serum vitamin B-12 concentration <148 pmol/L or a serum methylmalonic acid concentration >210 nmol/L-the maximum of the reference range for serum vitamin B-12-replete participants with normal creatinine.

    Results: After control for demographic characteristics, cancer, smoking, alcohol intake, serum ferritin, and serum creatinine, low versus normal vitamin B-12 status was associated with anemia [odds ratio (OR): 2.7; 95% CI: 1.7, 4.2], macrocytosis (OR: 1.8; 95% CI: 1.01, 3.3), and cognitive impairment (OR: 2.5; 95% CI: 1.6, 3.8). In the group with a low vitamin B-12 status, serum folate >59 nmol/L (80th percentile), as opposed to 59 nmol/L, was associated with anemia (OR: 3.1; 95% CI: 1.5, 6.6) and cognitive impairment (OR: 2.6; 95% CI: 1.1, 6.1). In the normal vitamin B-12 group, ORs relating high versus normal serum folate to these outcomes were <1.0 (Pinteraction < 0.05), but significantly <1.0 only for cognitive impairment (0.4; 95% CI: 0.2, 0.9).

    Conclusion: In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B-12 status was normal, however, high serum folate was associated with protection against cognitive impairment.

  8. Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine.

    Nilsson K, Gustafson L, and Hultberg B.
    International Journal of Geriatric Psychiatry. 2001;16:609-614.

    Abstract
    Objectives: To investigate the effect of cobalamin/folate supplementation on cognitive function in elderly patients with dementia. Method: The cobalamin/folate status of the patients was evaluated by measuring plasma homocysteine, serum methylmalonic acid, serum cobalamin and blood folate. Thirty-three patients were studied and repeatedly assessed with the Mini-Mental State Examination (MMSE) and 'A short cognitive performance test for assessing memory and attention' (SKT) during vitamin substitution. Results: Patients with mild-moderate dementia and elevated plasma homocysteine levels improved clinically with increased test scores after vitamin substitution, while severely demented patients and patients with normal plasma homocysteine levels did not improve clinically. CONCLUSIONS: Plasma homocysteine may be the best marker for detecting treatable cobalamin/folate deficiency in patients with dementia.

  9. Blood Folates Deficiencies and Cognitive Functions in Aging.

    Rapin JR, Le Poncin M, Grebyl J.
    In Steinhagen-Thiessen E and Knook DL, ed. Trends in Biomedical Gerontology. Vol. 1. Rijswijk, The Netherlands: TNO Institute for Experimental Gerontology; 1987:221-223.

    Folate deficiencies studied in 38 old persons (62 + 5 years) are accompanied by neuropsychiatric disturbances such as depression, asthenia, irritability, forgetfulness and lack of attention. These symptoms disappear with a treatment by folinic acid.

    [Chart] Folate boosts cognitive function in patients with memory loss

    High dose folate significantly improved:9
    - visual-spatial memory 3
    - perception and visual-spatial
    - organization 5
    - associative memory 10
    - logical reasoning 12
    - maze delay 13

    Lists of test in order without significant change:
    1-Rey auditory and verbal learning 2-stages of memorization visuo verbal, learning capacity, immediate and delayed recall, 4-verbal interferences, 8-psychomotor coordination, 9-object test, 11-verbal learning, 15-overlapped drawing and 16-perception and ability to discriminate figures. Not shown 6-reaction time test (visual), 7-reaction time test (auditory), 14-recall of visuo spatial memory.