Does Vitamin C Deficiency Affect Cognitive Development and Function?
Abstract
:1. Introduction
2. Vitamin C
3. The Functions of Vitamin C in the Brain
3.1. The Antioxidant Role of Vitamin C in the Brain
3.2. Vitamin C as a Neuromodulator
3.3. Vitamin C in Angiogenesis
4. Vitamin C Deficiency and Cognitive Dysfunction
4.1. Putative Consequences of Vitamin C Deficiency in the Developing Brain
Species | Intervention | Measurements | Outcome | Reference | |
---|---|---|---|---|---|
In Vivo Studies | |||||
SVCT2(−/−) mice (ED: 18.5–19.5). | Dams: 0.33 g/L VitC in drinking water. | VitC content, MDA, F2-isoprostanes and F4-neuroprostanes in brain (cortex). Additional IHC. | The SVCT2(−/−) fetuses: Increased F2-isoprostanes (p < 0.001), F4-neuroprostanesincreased (p < 0.05), isoketal staining, apoptotic cells and hemorrhages. Decreased collagen-IV staining and VitC content (p < 0.001). | [7] | |
Dunkin Hartley guinea pigs (6/7 to 60/61days). Postnatal deficiency. | VitC in diet: 923 mg/kg or 100 mg/kg feed. | Asc, DHA, glutathione, MDA and SOD in brain. Quantitation of hippocampal neurons. Functional assessment in MWM. | Decreased performance in MWM (p < 0.05) and reduced number of neurons in hippocampus (p < 0.05) in VitC deficient animals. | [1] | |
Dunkin Hartley guinea pigs (GD: 18). Prenatal deficiency. | VitC prenatal: 900 mg/kg diet or 100 mg/kg diet. Postnatal: 750 mg/kg or 100 mg/kg. | Asc, DHA and MDA in brain. Hippocampal neurogenesis and volume. Functional assessment in MWM. | Significant and persistent lower hippocampal volume (p < 0.001). | [9] | |
Dunkin Hartley guinea pigs (2 days to 3 weeks). | VitC in diet: 1036 mg/kg or 36 mg/kg. | Asc, DHA, glutathione, SOD, MDA, α- and γ-tocopherol, protein carbonyls, 8-oxo-deoxyguanosine and base excision repair in brain. | VitC deficiency caused significant reductions in Asc (p < 0.001), DHA (p = 0.034), MDA (p < 0.001) and protein carbonyls (p = 0.003) and an increase in base excision repair (p = 0.014). | [5] | |
Design and Subjects | Intervention | Measurements | Outcome | Reference | |
Clinical Studies | |||||
Cohort Studies | 92 preterm children (7.86 ± 0.7 years, birth weight: 1475.13 ± 556.44 g) 40 age-matched controls. | Cognitive testing: Spatial pattern/Recognition, Intradimensional/Extra Dimensional Set-Shifting task, Tower of London task, Spatial Working Memory task, Spatial Memory Span task, and a Psychomotor screening. | Preterm children had decreased performance in Psychomotor test (p < 0.01), Recognition test (p < 0.01), Spatial Memory Span (p < 0.01), and Spatial Working Memory (p < 0.001) | [90] | |
13 IUGR preterm infants (gestational age 33–34 weeks) and 12 controls. | Maternal blood, umbilical cord blood and placental samples: SOD, GSH-Px, MDA, AOP, ADA, CAT and XO. | All markers, except GSH-Px and AOP were elevated in umbilical cord blood. IUGR mothers differed significantly in all markers other than CAT. Placental samples were significantly changed in all markers, except SOD and ADA (p < 0.01 or less). | [96] | ||
Controlled trials | Randomized clinical trial: 160 women in high risk for pre-eclampsia (16–22 weeks pregnant) and 32 controls. | VitC (1000 mg/day) and VitE (400 IU/day) or placebo. | Plasma VitC, PAI-2, placenta growth factor, 8-epi-prostaglandin F2α, leptin, PAI-1/2 ratio. | Vitamin supplemented: VitC, 8-epi-prostaglandin F2α, leptin, and PAI-1/-2 equal to controls; whereas placebo-treated displayed decreased VitC, PAI-2, and placenta growth factor and increased 8-epi-prostaglandin F2α, leptin, and PAI 1/-2 ratio. | [104] |
Randomized clinical trial: 283 women with high risk of pre-eclampsia (16–22 weeks pregnant). | VitC (1000 mg/day) and VitE (400 IU/day) or placebo. | PAI-1 and -2 measured every month until delivery. Pre-eclampsia assessed by the development of proteinuric hypertension. | VitC + E supplementation was associated with a decrease in the PAI-1/PAI-2 ratio (p = 0.015) and a significantly decreased risk of pre-eclampsia (p = 0.002). | [107] | |
Double blind randomized clinical trial: 100 women in high risk of pre-eclampsia (14–20 weeks pregnant). | VitC (1000 mg/day) and VitE (400 IU/day) or placebo. | Incidence of pre-eclampsia. | No significant effect of VitC + E treatment. | [105] | |
Double blind randomized clinical trial: 1365 women in high risk for pre-eclampsia (14–22 weeks pregnant). | VitC (1000 mg/day) and VitE (400 IU/day) or placebo. | Occurrence of pre-eclampsia defined as hypertension and onset of proteinuria. | Supplementation with VitC + E did not reduce risk of pre-eclampsia. | [106] |
4.2. Vitamin C and Aging
Species | Intervention | Measurement | Outcome | Reference | |
---|---|---|---|---|---|
In vivo studies | |||||
APP/PSEN1 and B6C3F1/J mice (6–10 months). | VitC in diet (1 g/kg) and high or low dose VitE (750/400 IU/kg). | Functional assessment, amyloid, F4-neuroprostanes and MDA. | Supplementation with VitC and low VitE decreased markers of oxidative stress in transgenic mice (p < 0.05). Improvement of MWM performance was seen in low VitE group (0.05 > p < 0.001). | [127] | |
Swiss mice (3 and 7 months). | IP injection of 60 and 120 mg/kg VitC for three or eight consecutive days. | Elevated plus maze, passive avoidance test. | Treatment improved performance in young animals (p < 0.05) and reversed performance deficits in old animals (p < 0.05). | [111] | |
Dunkin Hartley guinea pig (3–9 months and 36–42 months). | Diet containing 325 mg VitC/kg or 100 mg VitC/kg. | VitC, MDA, glutathione, 8-oxodG and SOD in brain. SVCT2 mRNA expression in brain. | Deficiency did not cause significant changes in oxidative stress markers but aging per se showed a significant effect (p < 0.05). No detectable effect on SVCT mRNA expression in deficient. | [116] | |
AβPP mice (6–12 months). | 1333 mg/kg/day VitC in drinking water. | IHC for anti-Aβ, Western blot, Aβ-ELISA, OxyBlot, glutathione, functional assessment by MVM and elevated plus maze. | VitC prevented some behavioral abnormalities in AβPP mice (0.05 > p < 0.02), down-regulated amyloid (p < 0.05), significant difference of Aβ42/Aβ40 ratio (p < 0.02) and increased in synaptophysin (p < 0.05). Phosphorylated tau was decreased (p < 0.05). | [129] | |
Female ovariectomized Wistar rats (80 days). | VitE (40 mg/kg) and VitC (100 mg/kg) IP once daily for 30 days. | MWM, open field test. | Vitamin C + E treatment prevented deficits in reference memory in MWM (0.01 > p < 0.05). | [114] | |
Swiss mice (3 months). | VitC (60 mg/kg) IP injection of for three consecutive days. | Elevated plus maze and passive avoidance. | VitC injection reversed amnesia induced by scopolamine (0.4 mg/kg) and diazepam (1 mg/kg) (p < 0.05). | [111] | |
B6C3F1/J mice (12 weeks). | VitC (125 mg/kg) IP. | Behavioral testing, MDA and Asc content in cortex, AChE activity, brain glutathione. | VitC treatment reversed some of the memory deficits induced by scopolamine (1 mg/kg IP) (0.05 > p < 0.001) and increased medial forebrain AChE acticity (p < 0.001). | [130] | |
CD1 mice (16 months). | Oxiracetam (62.5/125/250 mg/kg), VitC (50/100/200 mg/kg), VitC (125 mg/kg) + oxiracetam (100 mg/kg) IP for three consecutive days. | Light-dark aversion test. | VitC alone or in combination with oxiracetam significantly reduced scopolamine-induced (0.25 mg/kg IP, day 4) amnesia (p < 0.01). | [136] | |
Dunkin Hartley guinea pigs (3–9 and 8–14 months). | Diet with 325 mg/kg VitC. | VitC in brain and CSF. | Concentrations of VitC significantly increased in CSF with age (p < 0.05). Elevated Asc oxidation ratio in young compared to old animals (p < 0.05). | [115] | |
Dunkin Hartley guinea pigs (3–9 and 36–42 months). | Diet with 325 mg VitC/kg or 100 mg VitC/kg. | VitC in CSF and 8-oxodG, MDA, glutathione and SOD in brain. | No effect was observed besides on VitC concentration in brain and CSF in deficient animals. | [116] | |
Design and Subjects | Intervention | Measurements | Outcome | Reference | |
Clinical Studies | |||||
Cohort studies | 12 AD or dementia patients (71 ± 11 years) and healthy controls (35 ± 5 years). | Blood samples of VitC and DHA. | Dementia and AD patients had significantly lower Asc and DHA levels (p < 0.001). | [137] | |
Patients (n = 134) (AD, vascular dementia or Parkinson’s) and 58 matching controls. | Plasma content of: α-carotene, β-carotene, lycopene, VitA, VitC, VitE and TAC. | VitC was significantly lower in AD (p < 0.001), vascular dementia (p < 0.001) and Parkinson’s disease with dementia (p < 0.01). | [117] | ||
Prospective cohort study: 633 participants age ≥65 years. | Direct inspection of ingested supplements (two weeks of base-line). Participants were followed for a mean of 4.3 years. | None of the VitE or VitC users developed AD despite a predicted incidence of 3.9 and 3.2, respectively (p = 0.04). | [132] | ||
Nurses’ Health study: 14,968 women age 70–79 in 1995–2000. | Semi-quantitative questionnaire on lifestyle, supplemental use and medical history biennially from 1980. | TICS, 10-word list, immediate and delayed recall, verbal fluency, digit span backwards test. | Long-term VitC + E supplementation was associated with better cognitive function (p = 0.03) and a trend toward better performance (p = 0.04) | [118] | |
The Honolulu-Asia Aging Study: 3385 men age 71–93 years. | Questionnaires on vitamin supplementation in 1982/1988. | Assessment of cognitive performance by CASI in 1991–1993. | VitC and/or VitE supplementation decreased the incidence of vascular (OR: 0.12) and mixed/other type dementia (OR: 0.31) and was associated with a higher cognitive performance (OR: 1.25). | [119] | |
The Rotterdam Prospective Study: 5395 participants age ≥55 years in 1990–1993 | Interview of dietary intake of VitC, VitE, β-carotene, supplements, educational level, etc. | Clinical examination and MMSE, GMS, CAMDEX in 1993–1994 and 1997–1999. | High dietary intake of VitC and VitE may lower the risk of Alzheimer’s disease. RR = +0.82/standard deviation increase in VitC intake. | [16] | |
Prospective cohort study: 32 patients with mild to moderate AD age 71 ± 7 years. | Physical examination. | ADAS-cog, MMSE, CDR and geriatric depression. CSF and blood samples at baseline. | CSF/Plasma VitC content predicted cognitive decline partially due to a compromised blood brain barrier integrity. | [15] | |
Nurses’ Health Study: 16,010 women age ≥70 years in 1995–2000. | Food-questionnaire in 1980 and expanded version in 1984, 1986, and every four years thereafter. FRAP assessment. | TICS scores and ten word list, global composite scores, East Boston Memory test on three occations. | No significant association between FRAP scores and cognitive function, when adjusted for confounders. | [138] | |
Adult Changes in Thought Prospective Study: 2969 participants age ≥65 years. | Self-reported VitC, VitE or multivitamin supplement. Participants were followed for a mean of 5.5 years. | Health and lifestyle parameters (e.g., BMI, smoking and alcohol consumption) CASI score every second year. | Neither VitC, VitE nor multivitamin use was associated with a decreased incidence of AD or dementia. | [133] | |
Prospective cohort study: 137 elderly age 66–90 years. | Nutritional data collected in 1980 and 1986. | Cognitive evaluation in Logical Memory, Abstraction and Visual Reproduction trials in 1986. | Plasma concentrations of VitC were positively correlated with Rey-Osterrieth Copy test performance and Visual Reproduction (p < 0.05). | [139] | |
Prospective cohort study: 921 elderly age ≥65 years. | A one week food diary or interviews to quantify consumer habits. Participants were followed for 20 years. | Medical examination including Hodkinson Abbreviated Mental test. | Participants with the lowest dietary/plasma VitC status had the poorest cognitive function (OR: 1.6). | [3] | |
Clinical trials | Randomized open-label clinical trial: 23 AD patients receiving cholinergic treatment. | 400 IU VitE and 1000 mg VitC per day or no vitamin treatment. CSF samples at baseline, one month and twelve months. | Clinical and neuropsychological assessment. | Significant increases in VitC content in CSF and decreases in autoxidation (p < 0.05). No neuropsychological differences. | [140] |
4.3. Vitamin C and Stroke
Species | Intervention | Measurement | Outcome | Reference | |
---|---|---|---|---|---|
In vivo studies | |||||
C57BL/6J mice. | DHA (40/250/500 mg/kg) or Asc (250/500 mg/kg) IV on three time points following MCAO. | Cortical cerebral blood flow, infarct volume, neurological assessment, mortality. | DHA improved cerebral blood flow dose-dependent. Decreased infarct size and mortality (p < 0.05). Asc did not show these effects. | [51] | |
SHR and SHR-SP rats (4–5 months old). | VitC (200 mg/kg) and VitE (100 mg/kg) PO once daily for 4 weeks MCAO of 24 h duration. | 2D Western blot of antioxidative protein expression, TAC, GSH-Px and MDA in brain. Cerebral infarct area. | VitC + E treatment significantly reduced oxidative stress and infarct area in SHR-SP (p < 0.01). | [52] | |
Male Sprague-Dawley rats (4 weeks old) with or without STZ-induced diabetes for six weeks | VitC (100 mg/kg) PO once daily for 2 weeks following MCAO/Re | Infarct volume and edema, neurological score. | VitC treatment significantly reduced infarct area, edema and neurological score in both non-diabetic and diabetic animals compared to untreated controls (p < 0.01). | [143] | |
Maccaca radiata monkey. | Ascorbate (500 mg/kg up to 2 g IV) immediately before MCAO of 4 h duration. | Cerebral infarct area. | VitC treatment significantly reduced infarct area (p = 0.0003). | [142] | |
Design and Subjects | Intervention | Measurements | Outcome | Reference | |
Clinical Studies | |||||
Cohort studies | Department of Health and Social Security nutritional survey: 730 participants age ≥65 years. | Food diary and interviews. Participants were followed for 20 years. | Plasma VitC, physical examination. | Participants in the highest third of VitC intake had a RR = 0.5, when compared with the lowest third. | [146] |
The Nurses’ Health Study: 85,118 participants age 30–55 years. | Semi-quantitative questionnaire on lifestyle, supplemental use and medical history. The participants were followed for 16 years. | VitC supplemental use is significantly associated with lower risk of coronary heart disease (RR = 0.72). | [147] | ||
Cancer-Norfolk prospective study: 20,649 participants age 40–79 years. | Health and lifestyle questionnaire, socioeconomic data | Physical examination, plasma VitC content. | Plasma VitC was inversely related to risk of stroke. Participants in top quantile had a RR = 0.58. | [145] | |
Basel prospective study 2974 men | The participants were followed for 12 years. | Baseline values of VitC and β-carotene in plasma. | Low levels of VitC and β-carotene were related to an increased risk of dying from ischemic heart disease or stroke. | [50] | |
Clinical trials | Double-blind randomized clinical trial: 40 patients (0–2 years after cardiac transplant). | 500 mg VitC and 400 IU VitE twice daily for one year or placebo. | Plasma VitC and VitE content. Average intimal index, coronary endothelium-dependent vasoreactivity. | Supplementation with VitC + E caused retardation of early signs of atherosclerosis associated with heart transplantation (p = 0.008). | [148] |
Sixty ischemic stroke patients (72.8 ± 10.4 years), VitC vs. non-VitC group and 20 controls (69.8 ± 10.5 years). | 500 mg/day VitC IV in addition to standard stroke treatment for ten days starting the day after stroke. | NIHSS neurological status and bilirubin, creatinine, uric acid, and TAC day one, three, five and ten of treatment. NIHSS three months after stroke. | No difference in clinical status of patients during the ten day treatment or after the three months follow-up. | [144] |
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Hansen, S.N.; Tveden-Nyborg, P.; Lykkesfeldt, J. Does Vitamin C Deficiency Affect Cognitive Development and Function? Nutrients 2014, 6, 3818-3846. https://doi.org/10.3390/nu6093818
Hansen SN, Tveden-Nyborg P, Lykkesfeldt J. Does Vitamin C Deficiency Affect Cognitive Development and Function? Nutrients. 2014; 6(9):3818-3846. https://doi.org/10.3390/nu6093818
Chicago/Turabian StyleHansen, Stine Normann, Pernille Tveden-Nyborg, and Jens Lykkesfeldt. 2014. "Does Vitamin C Deficiency Affect Cognitive Development and Function?" Nutrients 6, no. 9: 3818-3846. https://doi.org/10.3390/nu6093818