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Cited by 813Folate and B Vitamins ResearchDementia and Cognitive Impairment ResearchAlcoholism and Thiamine Deficiency

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Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial

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Smith, A. David, Smith, Stephen M., de Jager, Celeste A., Whitbread, Philippa, Johnston, Carole, Agacinski, Grzegorz, Oulhaj, Abderrahim, Bradley, Kevin M., Jacoby, Robin, Refsum, Helga·2010·PLoS ONE
DOI 10.1371/journal.pone.0012244PMC PMC2935890
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Abstract

BACKGROUND: An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins. OBJECTIVE: To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159). METHODS AND FINDINGS: Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B(6) and B(12) in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B(12) (0.5 mg/d) and vitamin B(6) (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans. RESULTS: A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63-0.90] in the active treatment group and 1.08% [0.94-1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category. CONCLUSIONS AND SIGNIFICANCE: The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer's disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer's disease, trials are needed to see if the same treatment will delay the development of Alzheimer's disease. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN94410159.

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Crossref · 10.1371/journal.pone.0012244

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Figures

Figure 1 Participant Flow in the trial.
Figure 1 Participant Flow in the trial.CC BY · PubMed Central
Figure 2 Atrophy rate by baseline homocysteine. Linear regression lines with 95% mean prediction intervals. R2 for placebo group (n = 83) was 0.242 (P<0.001); for the treatment group (n = 85) R2 was 0.001 (P = 0.74). The x-axis is a logarithmic scale labelled with linear values.
Figure 2 Atrophy rate by baseline homocysteine. Linear regression lines with 95% mean prediction intervals. R2 for placebo group (n = 83) was 0.242 (P<0.001); for the treatment group (n = 85) R2 was 0.001 (P = 0.74). The x-axis is a logarithmic scale labelled with linear values.CC BY · PubMed Central
Figure 3 Atrophy rate by change in plasma total homocysteine over a two year period. Subjects in this analysis were a subset (66 in placebo; 70 in the active treatment) who showed biochemical evidence of good compliance (see Table 3). Linear regression with 95% mean prediction intervals, adjusted for age at baseline; partial r = 0.22, P = 0.011. The x-axis is a logarithmic scale labelled with linear values.
Figure 3 Atrophy rate by change in plasma total homocysteine over a two year period. Subjects in this analysis were a subset (66 in placebo; 70 in the active treatment) who showed biochemical evidence of good compliance (see Table 3). Linear regression with 95% mean prediction intervals, adjusted for age at baseline; partial r = 0.22, P = 0.011. The x-axis is a logarithmic scale labelled with linear values.CC BY · PubMed Central
Figure 4 Selected subtraction MRI scans. The images are from the baseline scan with colour superimposed to show the brain tissue change over the following two years. Colours show expansion (red/yellow) or contraction (blue/light blue) of the brain of 0.3 to 1.0 mm, with the lightest colour indicating the biggest change. (A) Subtraction image of female participant in the placebo group, age 79 years, with baseline tHcy of 22 µmol/L, whose tHcy concentration increased by 8 µmol/L over two years. Atrophy rate was 2.50% per year. Atrophy most strongly appears here as enlargement of the ventricles. (B) Subtraction image of female participant in active treatment group, age 72 years, with baseline tHcy of 24 µmol/L at baseline, whose tHcy concentration decreased by 12 µmol/L over two years. Atrophy rate 0.46% per year. There is no clear visible pattern of atrophy.
Figure 4 Selected subtraction MRI scans. The images are from the baseline scan with colour superimposed to show the brain tissue change over the following two years. Colours show expansion (red/yellow) or contraction (blue/light blue) of the brain of 0.3 to 1.0 mm, with the lightest colour indicating the biggest change. (A) Subtraction image of female participant in the placebo group, age 79 years, with baseline tHcy of 22 µmol/L, whose tHcy concentration increased by 8 µmol/L over two years. Atrophy rate was 2.50% per year. Atrophy most strongly appears here as enlargement of the ventricles. (B) Subtraction image of female participant in active treatment group, age 72 years, with baseline tHcy of 24 µmol/L at baseline, whose tHcy concentration decreased by 12 µmol/L over two years. Atrophy rate 0.46% per year. There is no clear visible pattern of atrophy.CC BY · PubMed Central

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Metadata

Authors
Smith, A. D., Smith, S. M., de Jager, C. A., Whitbread, P., Johnston, C., Agacinski, G., Oulhaj, A., Bradley, K. M., Jacoby, R., & Refsum, H.
Affiliations
  • University of Oxford (GB)
  • University of Oslo (NO)
Corresponding author
Smith, A. David
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2010-09-08
Volume
5
Issue
9
Pages
e12244
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0012244
PMC
PMC2935890
OpenAlex
W2156635660
Cited by
813
References
49
Citations by year
2026: 50 · 2025: 49 · 2024: 34 · 2023: 44 · 2022: 58 · 2021: 58 · 2020: 66 · 2019: 39 · 2018: 43 · 2017: 55 · 2016: 59 · 2015: 49 · 2014: 44 · 2013: 58 · 2012: 59
FWCI
36.35
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Alzheimer's Research Trust
  • National Institute for Health and Care Research
  • University of Oxford
  • Medical Research Council
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Clinical Neurology › Alcoholism and Thiamine Deficiency
Keywords
homocysteine, B vitamins, folic acid, vitamin B6, vitamin B12, brain atrophy, mild cognitive impairment, cognitive decline, dementia prevention, older adults, plasma homocysteine, volumetric MRI, cognitive performance, adverse events
MeSH terms
Aged, Aged, 80 and over, Atrophy, Brain, Cognition Disorders, Female, Homocysteine, Humans, Magnetic Resonance Imaging, Male, Radiography, Vitamin B Complex, Treatment Outcome

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