Table 2.
Clinical studies in humans linking methyl-donor supplementation with neurodevelopment and cognition
| Reference | Behavioral test | Supplementation period | Nutrient(s) supplemented or analyzed | Outcomes |
|---|---|---|---|---|
| Boeke et al. (2013)23 | Offspring visual memory and intelligence | Pregnancy (1st and 2nd trimesters) | Analyzed: choline, vitamin B12, betaine, and folate (maternal intake questionnaire) | Increased gestational choline intake was associated with better visual memory at age 7; no associations for other methyl donors |
| Wu et al. (2012)51 | Bayley Scales of Infant Development, Third Edition | Pregnancy (2nd trimester) | Analyzed: choline, betaine, dimethylglycine, methionine, homocysteine, cysteine, vitamin B12, holotranscobalamin, and folate (maternal plasma) | Maternal plasma free choline and betaine in the first half of pregnancy associated with increased infant cognitive test scores |
| Valera-Gran et al. (2014)52 | Bayley Scales of Infant Development (1 y) | Pregnancy | Analyzed: folic acid (maternal intake questionnaire) | Children from mothers who consumed over 5000 µg of folic acid daily had lower psychomotor scores and increased risk for delayed psychomotor development |
| Signore et al. (2008)53 | Intelligence quotient (5 y) | Pregnancy | Analyzed: choline (maternal cord blood) | No correlations found |
| Julvez et al. (2009)54 | McCarthy Scale of Children's Abilities (4 y) | Pregnancy (1st trimester) | Analyzed: folic acid supplementation (maternal intake questionnaire) | Reported folic acid supplement use during pregnancy was associated with improved neurodevelopment and decreased inattention symptoms |
| Roth et al. (2011)55 | Children’s language competency (3 y) | Pregnancy (4 wk before conception to 8 wk after conception) | Analyzed: folic acid supplementation (maternal intake questionnaire) | Folic acid supplementation during early pregnancy was associated with reduced risk of severe language delay |
| Veena et al. (2010)56 | Cognitive function assessment—memory, attention and fluid reasoning (9–10 y) | Pregnancy (30 wk) | Analyzed: folic acid, vitamin B12 and homocysteine (maternal plasma) | Increased folic acid concentrations associated with increased cognitive test scores; no associations were seen with vitamin B12 or homocysteine |
| Chatzi et al. (2012)57 | Bayley Scales of Infant Development, Third Edition (18 mo) | Pregnancy (14–18 wk) | Analyzed: folic acid supplementation (maternal intake questionnaire and RBC concentration) | Folic acid supplementation (5 mg/d) was associated with enhanced vocabulary development, communication skills, and verbal comprehension |
| Villamor et al. (2012)58 | Peabody Picture Vocabulary Test III and Wide Range Assessment of Visual Motor Abilities (3 y) | Pregnancy (1st and 2nd trimesters) | Analyzed: folic acid, vitamin B12, choline, betaine, and methionine (maternal intake questionnaire) | Higher folate intake in 1st trimester was associated with higher receptive language; weak inverse association between vitamin B12 intake during 2nd trimester and receptive language; no association with choline, betaine, or methionine |
| Cheatham et al. (2012)59 | Short-term visuospatial memory, long-term episodic memory, language development, and global development | Pregnancy + lactation (18 wk gestation to 90 d post partum) | Supplemented: phosphatidylcholine | No effects seen |
| Prado et al. (2017)60 | General intellectual ability, declarative memory, procedural memory, executive function, academic achievement, fine motor dexterity, and socioemotional health (9–12 y) | Pregnancy + lactation (pregnancy + 3 mo post partum) | Supplemented: multiple micronutrients (iron, folic acid, retinol, vitamins D, E, C, B1, B2, B6, B12, zinc, copper, selenium, and iodine) or iron and folic acid | Supplementation with multiple micronutrients increased child cognitive development more than that with iron and folic acid alone |
| Ross et al. (2016)61 | Child Behavior Checklist (40 mo) | Pregnancy + lactation (2nd trimester to 3 mo) | Supplemented: phosphatidylcholine | Phosphatidylcholine supplementation decreased attention problems and social withdrawal |
| Nguyen et al. (2016)62 | Memory, executive function, attention, and hyperactivity | Early life (5–10 y) | Supplemented: choline (6 wk) | No effects seen |
| Strain et al. (2013)63 | Finger tapping test, Preschool Language Scale–Revised, Woodcock-Johnson Test of Scholastic Achievement, Child Behavior Checklist, and Kaufman Brief Intelligence Test | Early life (5 y) | Analyzed: choline, betaine, dimethylglycine, methionine, and homocysteine (plasma) | No associations found |
| Rauh-Pfeiffer et al. (2014)64 | HAWIVA-III, WPPSI-III, Kaufman Assessment Battery for Children | Early life (4–6 y) | Supplemented: folic acid, riboflavin, pyridoxine, cobalamin, and calcium lactate pentahydrate (3 mo) | Supplementation decreased plasma homocysteine concentration, but no changes were seen in cognitive performance |
| Lefèvra-Arbogast et al. (2016)30 | Dementia | Adult | Analyzed: folic acid, vitamins B6 and B12 (24-h recall) | Higher folate intakes associated with decreased risk of dementia; no associations found for vitamin B6 or B12 |
| Morris et al. (2010)65 | Wechsler Adult Intelligence Scale III | Adult (≥ 60 y) | Analyzed: folic acid, vitamin B12, and 5-MeTHF (serum) | Normal vitamin B12 status together with higher serum 5MeTHF associated with higher cognitive test scores |
| Morris et al. (2007)66 | Wechsler Adult Intelligence Scale III | Adult (≥ 60 y) | Analyzed: folic acid and vitamin B12 (serum) | Low vitamin B12 together with high serum folate associated with cognitive impairment; normal vitamin B12 status together with high serum folate associated with protection against cognitive impairment |
| Wald et al. (2010)67 | Cognitive function test scores (3 y from start of treatment) | Adult (≥45 y) | Analyzed: meta-analysis of 9 placebo-controlled randomized trials, supplementing folic acid with or without other B vitamins | No associations found |
| Durga et al. (2007)68 | Performance for memory, sensorimotor speed, complex speed, information processing speed, and word fluency | Adult (50–70 y) | Supplemented: folic acid (3 y) | 3-y changes in memory, information processing speed, and sensorimotor speed were significantly better in the folic acid–supplemented group |
| Walker et al. (2012)69 | Telephone Interview for Cognitive Status–Modified, the Brief Test of Adult Cognition by Telephone, and the Informant Questionnaire on Cognitive Decline in the Elderly | Adult (60–74 y) | Supplemented: folic acid and vitamin B12 (2 y) | Long-term supplementation of daily oral folic acid and vitamin B12 improved immediate and delayed memory performance; no differences seen in orientation, attention, semantic memory, processing speed, or informant reports |
| de Koning et al. (2016)70 | Geriatric Depression Scale | Adult (≥ 65 y) | Supplemented: folic acid and vitamin B12 (2 y) | No changes in depressive symptoms observed |
| Zhang et al. (2017)31 | MMSE | Adult (≈ 75 y) | Analyzed: meta-analysis of 77 studies, supplementing folic acid, and vitamin B12 and/or vitamin B6 (supplementation length varied from 6 to 18 mo) | No associations found |
| Clarke et al. (2014)71 | Specific cognitive domains and MMSE | Adult (≈ ≥60 y) | Analyzed: meta-analysis of 11 studies, supplementing B vitamins (supplementation length varied from 0.3 to 7 y) | No associations found |
| Porter et al. (2017)72 | MMSE, RBANS, and the Frontal Assessment Battery | Adult (≥ 60 y) | Analyzed: folate, vitamins B12, B6, B2, and homocysteine (at 5-y follow-up) | Lower vitamin B6 status was associated with accelerated rate of cognitive decline as assessed by RBANS and MMSE; lower vitamin B2 status was associated with accelerated rate of cognitive decline as assessed by RBANS, but not MMSE |
Abbreviations: HAWIVA-III, Hannover-Wechsler-Intelligenztest für das Vorschulalter; MMSE, Mini Mental State Examination; RBC, red blood cell; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence, 3rd edition; 5-MeTHF, 5-methyltetrahydrofolate.