Andrew H. Ford

Effect of Homocysteine Lowering Treatment on Cognitive Function: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Elevated total plasma homocysteine has been linked to the development of cognitive impairment and dementia in later life and this can be reliably lowered by the daily supplementation of vitamin B6, B12, and folic acid. We performed a systematic review and meta-analysis of 19 English language randomized, placebo-controlled trials of homocysteine lowering B-vitamin supplementation of individuals with and without cognitive impairment at the time of study entry. We standardized scores to facilitate comparison between studies and to enable us to complete a meta-analysis of randomized trials. In addition, we stratified our analyses according to the folate status of the country of origin. B-vitamin supplementation did not show an improvement in cognitive function for individuals with (SMD = 0.10, 95%CI -0.08 to 0.28) or without (SMD = -0.03, 95%CI -0.1 to 0.04) significant cognitive impairment. This was irrespective of study duration (SMD = 0.05, 95%CI -0.10 to 0.20 and SMD = 0, 95%CI -0.08 to 0.08), study size (SMD = 0.05, 95%CI -0.09 to 0.19 and SMD = -0.02, 95%CI -0.10 to 0.05), and whether participants came from countries with low folate status (SMD = 0.14, 95%CI -0.12 to 0.40 and SMD = -0.10, 95%CI -0.23 to 0.04). Supplementation of vitamins B12, B6, and folic acid alone or in combination does not appear to improve cognitive function in individuals with or without existing cognitive impairment. It remains to be established if prolonged treatment with B-vitamins can reduce the risk of dementia in later life.

Vitamins B12, B6, and folic acid for cognition in older men.

Objective: To investigate whether supplementing older men with vitamins B12, B6, and folic acid improves cognitive function. Methods: The investigators recruited 299 community-representative hypertensive men 75 years and older to a randomized, double-blind controlled clinical trial of folic acid, vitamin B6, and B12 supplementation vs placebo over 2 years. The primary outcome of interest was the change in the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog). A secondary aim of the study was to determine if supplementation with vitamins decreased the risk of cognitive impairment and dementia over 8 years. Results: The groups were well-balanced for demographic and biochemical parameters. There was no difference in the ADAS-cog change from baseline to 24 months between the placebo (0.8, SD 4.0) and vitamins group (0.7, SD 3.4). The adjusted scores in the treatment groups did not differ over time (placebo 0.2 lower, z = 0.71, p = 0.478). There was a nonsignificant 28% decrease in the risk of cognitive impairment (odds ratio 0.72, 95% confidence interval 0.25–2.09) and dementia (hazard ratio 0.72, 95% confidence interval 0.29–1.78) over 8 years of follow-up. Conclusions: The daily supplementation of vitamins B12, B6, and folic acid does not benefit cognitive function in older men, nor does it reduce the risk of cognitive impairment or dementia. Classification of evidence: This study provides Class I evidence that vitamin supplementation with daily doses of 400 μg of B12, 2 mg of folic acid, and 25 mg of B6 over 2 years does not improve cognitive function in hypertensive men aged 75 and older.

Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression.

BACKGROUND Folate and vitamin B12 insufficiencies have been associated with increased risk of depression. This systematic review aimed to clarify if, compared with placebo, treatment with folate and/or vitamin B12 reduces depression scale scores, increases remission, and prevents the onset of clinically significant symptoms of depression in people at risk. METHODS This systematic review searched the PubMed, PsychInfo, Embase, and Cochrane databases from inception to 6 June 2014, using the following terms and strategy: (vitamin B12 or vitamin B9 or folate or folic acid or cobalamin or cyanocobalamin) and (depression or depressive disorder or depressive symptoms) and (randomized controlled trial or RCT). The electronic search was supplemented by manual search. Two independent reviewers assessed all papers retrieved for eligibility and bias, and extracted crude data. Review Manager 5 was used to manage and analyze the data. RESULTS Two hundred and sixty-nine manuscripts were identified, of which 52 were RCTs and 11 fulfilled criteria for review. We found that the short-term use of vitamins (days to a few weeks) does not contribute to improve depressive symptoms in adults with major depression treated with antidepressants (5 studies, standardized mean difference = -0.12, 95% confidence interval--95% CI = -0.45, 0.22), but more prolonged consumption (several weeks to years) may decrease the risk of relapse (1 study, odds ratio (OR) = 0.33, 95% CI = 0.12, 0.94) and the onset of clinically significant symptoms in people at risk (2 studies, risk ratio = 0.65, 95% CI = 0.43, 0.98). CONCLUSIONS The number of available trials remains small and heterogeneity between studies high. The results of these meta-analyses suggest that treatment with folate and vitamin B12 does not decrease the severity of depressive symptoms over a short period of time, but may be helpful in the long-term management of special populations.

Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and cognitive impairment: the health in men study

High total plasma homocysteine (tHcy) has been associated with cognitive impairment in later life, but it is unclear if this association is causal or is due to confounding. The C677T polymorphism of the 5,10 methylenetetrahydrofolate reductase gene (MTHFR) increases basal tHcy, but its contribution to cognitive impairment has not been established. We designed this study to determine if tHcy is causally related to cognitive impairment in later life by investigating its association with high tHcy and the MTHFR-C677T polymorphism. We recruited 1778 older men from the Health in Men Study cohort and established caseness on the basis of the participants’ scores on a Telephone Interview for Cognitive Status score ⩽27 in 2008. Exposure to tHcy, gene status and other variables of interest were obtained from assessments 4–7 years earlier. Multivariate logistic regression showed that the odds of cognitive impairment increased with a doubling of tHcy (adjusted odds ratio, OR 1.36; 95% confidence interval, 95% CI 1.02–1.82). Compared with the wild CC genotype, participants with the MTHFR-TT genotype had 46% greater odds of cognitive impairment (OR 1.46, 95% CI 1.01–2.11, P=0.043). The results of this study are consistent with, but do not prove the hypothesis that high tHcy causes cognitive impairment in later life.

Effect of B Vitamins and Lowering Homocysteine on Cognitive Impairment in Patients With Previous Stroke or Transient Ischemic Attack A Prespecified Secondary Analysis of a Randomized, Placebo-Controlled Trial and Meta-Analysis

Background and Purpose— High plasma total homocysteine (tHcy) has been associated with cognitive impairment but lowering tHcy with B-vitamins has produced equivocal results. We aimed to determine whether B-vitamin supplementation would reduce tHcy and the incidence of new cognitive impairment among individuals with stroke or transient ischemic attack ≥6 months previously. Methods— A total of 8164 patients with stroke or transient ischemic attack were randomly allocated to double-blind treatment with one tablet daily of B-vitamins (folic acid, 2 mg; vitamin B6, 25 mg; vitamin B12, 500 &mgr;g) or placebo and followed up for 3.4 years (median) in the VITAmins TO Prevent Stroke (VITATOPS) trial. For this prespecified secondary analysis of VITATOPS, the primary outcome was a new diagnosis of cognitive impairment, defined as a Mini-Mental State Examination (MMSE) score <24 on ≥2 follow-up visits. Secondary outcomes were cognitive decline, and the mean tHcy and MMSE at final follow-up. Results— A total of 3089 participants (38%) voluntarily undertook the MMSE >6 months after the qualifying stroke; 2608 participants were cognitively unimpaired (MMSE ≥24), of whom 2214 participants (1110 B-vitamins versus 1104 placebo) had follow-up MMSEs during 2.8 years (median). At final follow-up, allocation to B-vitamins, compared with placebo, was associated with a reduction in mean tHcy (10.2 &mgr;mol/L versus 14.2 &mgr;mol/L; P<0.001) but no change from baseline in the mean MMSE score (−0.22 points versus −0.25 points; difference, 0.03; 95% confidence interval, −0.13 to 0.19; P=0.726) and no difference in the incidence of cognitive impairment (5.51% versus 5.47%; risk ratio, 1.01; 95% confidence interval, 0.69–1.48; P=0.976), cognitive decline (9.1% versus 10.3%; risk ratio, 0.89; 0.67–1.18; P=0.414), or cognitive impairment or decline (11.0% versus 11.3%; risk ratio, 0.98; 0.75–1.27; P=0.855). Conclusions— Daily supplementation with folic acid, vitamin B6, and vitamin B12 to a self-selected clinical trial cohort of cognitively unimpaired patients with previous stroke or transient ischemic attack lowered mean tHcy but had no effect on the incidence of cognitive impairment or cognitive decline, as measured by the MMSE, during a median of 2.8 years. Clinical Trial Registration— URL: http://www.controlled-trials.com. Unique identifier: ISRCTN74743444; URL: http://www.clinicaltrials.gov. Unique identifier: NCT00097669.

B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: results from the B-VITAGE randomised, double-blind, placebo-controlled trial

BACKGROUND Depression is common and the efficacy of antidepressants is suboptimal. High plasma homocysteine has been consistently associated with depression, and treatment with certain B vitamins demonstrably reduces its concentration. AIMS To determine whether vitamins B6, B12 and folic acid enhance response to antidepressant treatment over 52 weeks. METHOD Randomised, double-blind, placebo-controlled trial of citalopram (20-40 g) together with 0.5 mg of vitamin B12, 2 mg of folic acid and 25 mg of vitamin B6 for 52 weeks (Australian and New Zealand Clinical Trials Registry: 12609000256279). Participants were community-dwelling adults aged 50 years or over with DSM-IV-TR major depression. We measured severity of symptoms with the Montgomery-Åsberg Depression Rating Scale (MADRS). The primary outcome was remission of the depressive episode after 12, 26 and 52 weeks. Secondary outcomes included reduction of MADRS scores over time and relapse of major depression after recovery by week 12. Results In total, 153 people were randomised (76 placebo, 77 vitamins). Remission of symptoms was achieved by 78.1 and 79.4% of participants treated with placebo and vitamins by week 12 (P = 0.840), by 76.5 and 85.3% at week 26 and 75.8 and 85.5% at week 52 (effect of intervention over 52 weeks: odds ratio (OR) = 2.49, 95% CI 1.12-5.51). Group differences in MADRS scores over time were not significant (P = 0.739). The risk of subsequent relapse among those who had achieved remission of symptoms at week 12 was lower in the vitamins than placebo group (OR = 0.33, 95% CI 0.12-0.94). CONCLUSIONS B vitamins did not increase the 12-week efficacy of antidepressant treatment, but enhanced and sustained antidepressant response over 1 year. Replication of these findings would mandate that treatment guidelines adopt the adjunctive use of B vitamins as a safe and inexpensive strategy to manage major depression in middle-aged and older adults.

Plasma homocysteine and MTHFRC677T polymorphism as risk factors for incident dementia

Background Elevated total plasma homocysteine (tHcy) has been associated with increased risk of dementia. The C677T polymorphism of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) increases tHcy and provides a means of studying the association between tHcy and dementia while not being as susceptible to the common biases and confounding of observational studies. The authors designed this longitudinal study to determine if high tHcy and the MTHFR C677T polymorphism increase the risk of incident dementia among older men. Methods The authors studied 4227 men aged 70–89 years from the Health in Men Study cohort and established the diagnosis of dementia (International Classification of Diseases—10th edition) using morbidity and mortality records. Information on tHcy, MTHFR gene status, lifestyle and clinical variables were obtained using postal and face-to-face assessments. Results 230 men (5.4%) developed dementia during the mean follow-up period of 5.8±1.6 years (range 0.1–8.2 years). The hazard of dementia increased with a doubling of tHcy concentration (adjusted HR 1.48, 95% CI 1.10 to 2.00) and was higher in men with tHcy >15 μmol/l (adjusted HR 1.36 95% CI 1.03 to 1.81, p=0.032). Men with the TT genotype had a HR of dementia of 1.25 (95% CI 0.81 to 1.92). Conclusions The results of this prospective study are consistent with a causal link between high tHcy and incident dementia, but the study lacked power to determine an effect of the MTHFR genotype.

Homocysteine, depression and cognitive function in older adults.

BACKGROUND Depression and high total plasma homocysteine (tHcy) are independently associated with cognitive impairment in older adults. We designed this study to determine if high tHcy is a mediator of cognitive performance in older adults with major depression. METHODS We recruited 358 community-dwelling older adults experiencing depressive symptoms, 236 (65.9%) of who met DSM-IV-TR criteria for major depression. Assessment included the Montgomery Asberg Depression Rating Scale (MADRS), fasting tHcy and the Consortium to Establish a Registry for Alzheimers Disease neuropsychological battery. RESULTS Individuals with major depression and high tHcy had significantly worse immediate verbal and delayed visual recall. Non-depressed participants with high tHcy had lower MMSE, immediate and delayed recall scores than those with normal tHcy. The odds of cognitive inefficiency for those with high tHcy was nearly doubled for the MMSE (OR 1.9, 95%CI 1.1-3.3), immediate (OR 1.9, 95%CI 1.1-3.5) and delayed (OR 1.9, 95%CI 1.1-3.4) word recall after adjusting for age, gender, IHD and MADRS score. LIMITATIONS The presence of sub-syndromal depressive symptoms in our non-depressed group and exclusion of participants with established cognitive impairment may limit the generalizability of this study. CONCLUSIONS Elevated tHcy was associated with weaker performance in tests of immediate and delayed memory and global cognitive performance when compared to those with normal tHcy independent of the presence of major depression or the severity of depressive symptoms. Homocysteine lowering B-vitamin supplementation may offer a potential therapeutic target to try and mitigate the often-disabling impact of cognitive deficits found in this population.

Rapid eye movement sleep behavior disorder in Parkinson's disease: magnetic resonance imaging study.

Rapid eye movement sleep behavior disorder has poor prognostic implications for Parkinsons disease. The authors recruited 124 patients with early Parkinsons disease to compare clinical and neuroimaging findings based on the presence of this sleep disorder.

Rapid eye movement sleep behavior disorder in Parkinson's disease

Rapid eye movement sleep behavior disorder has poor prognostic implications for Parkinsons disease. The authors recruited 124 patients with early Parkinsons disease to compare clinical and neuroimaging findings based on the presence of this sleep disorder.