Aggressive Behaviors in Alzheimer Disease and Mild Cognitive Impairment: Systematic Review and Meta-Analysis.

OBJECTIVE: We aim to estimate the risk of perpetrating aggression in Alzheimer disease (AD) and mild cognitive impairment (MCI) by conducting a systematic review and meta-analysis of primary studies. METHODS: A systematic search was conducted in six bibliographic databases according to a preregistered protocol. Studies that reported aggressive behaviors in individuals with AD and MCI compared with healthy individuals or those with other dementia etiologies were identified. Risks of aggressive behaviors were assessed using random effects models to calculate pooled odds ratios (ORs). Publication bias was examined. RESULTS: In total, 17 studies involving 6,399 individuals with AD and 2,582 with MCI were identified. Compared with healthy individuals, significantly increased risks of aggressive behaviors were found in AD (OR, 4.9, 95% CI, 1.8-13.2) but not in MCI (OR, 1.8, 95% CI, 0.7-4.3). When comparing AD with MCI, the risk in AD was higher (OR, 2.6, 95% CI, 1.7-4.0). We found no differences in risk of aggressive behaviors between AD and other dementia subtypes or between amnestic and nonamnestic MCI. CONCLUSION: Individuals with AD are at higher risk of manifesting aggressive behaviors than healthy individuals or those with MCI. Our findings not only underscore the necessity of treatment of aggressive behaviors in AD but also highlight the importance of preventing the transition from MCI to AD.

Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment.

Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer's disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.

Donepezil and memantine for moderate-to-severe Alzheimer's disease.

BACKGROUND: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. METHODS: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. RESULTS: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. CONCLUSIONS: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.).

Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial.

BACKGROUND: Homocysteine is a risk factor for Alzheimer's disease. In the first report on the VITACOG trial, we showed that homocysteine-lowering treatment with B vitamins slows the rate of brain atrophy in mild cognitive impairment (MCI). Here we report the effect of B vitamins on cognitive and clinical decline (secondary outcomes) in the same study. METHODS: This was a double-blind, single-centre study, which included participants with MCI, aged ≥ 70 y, randomly assigned to receive a daily dose of 0.8 mg folic acid, 0.5 mg vitamin B(12) and 20 mg vitamin B(6) (133 participants) or placebo (133 participants) for 2 y. Changes in cognitive or clinical function were analysed by generalized linear models or mixed-effects models. RESULTS: The mean plasma total homocysteine was 30% lower in those treated with B vitamins relative to placebo. B vitamins stabilized executive function (CLOX) relative to placebo (P = 0.015). There was significant benefit of B-vitamin treatment among participants with baseline homocysteine above the median (11.3 µmol/L) in global cognition (Mini Mental State Examination, P < 0.001), episodic memory (Hopkins Verbal Learning Test-delayed recall, P = 0.001) and semantic memory (category fluency, P = 0.037). Clinical benefit occurred in the B-vitamin group for those in the upper quartile of homocysteine at baseline in global clinical dementia rating score (P = 0.02) and IQCODE score (P = 0.01). CONCLUSION: In this small intervention trial, B vitamins appear to slow cognitive and clinical decline in people with MCI, in particular in those with elevated homocysteine. Further trials are needed to see if this treatment will slow or prevent conversion from MCI to dementia.

Determining the minimum clinically important differences for outcomes in the DOMINO trial.

BACKGROUND: Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes, whether or not a treatment has delivered a specified minimum clinically important difference (MCID) is also relevant to patients and their caregivers and doctors. Many dementia treatment randomised controlled trials (RCTs) have not reported MCIDs and, where they have been done, observed differences have not reached these. METHODS: As part of the development of the Statistical Analysis Plan for the DOMINO trial, investigators met to consider expert opinion- and distribution-based values for the MCID and triangulated these to provide appropriate values for three outcome measures, the Standardised Mini-mental State Examination (sMMSE), Bristol Activities of Daily Living Scale (BADLS) and Neuropsychiatric Inventory (NPI). Only standard deviations (SD) were presented to investigators who remained blind to treatment allocation. RESULTS: Adoption of values for MCIDs based upon 0.4 of the SD of the change in score from baseline on the sMMSE, BADLS and NPI in the first 127 participants to complete DOMINO yielded MCIDs of 1.4 points for sMMSE, 3.5 for BADLS and 8.0 for NPI. CONCLUSIONS: Reference to MCIDs is important for the full interpretation of the results of dementia trials and those conducting such trials should be open about the way in which they have determined and chosen their values for the MCIDs.

Donepezil for the treatment of agitation in Alzheimer's disease.

BACKGROUND: Agitation is a common and distressing symptom in patients with Alzheimer's disease. Cholinesterase inhibitors improve cognitive outcomes in such patients, but the benefits of these drugs for behavioral disturbances are unclear. METHODS: We randomly assigned 272 patients with Alzheimer's disease who had clinically significant agitation and no response to a brief psychosocial treatment program to receive 10 mg of donepezil per day (128 patients) or placebo (131 patients) for 12 weeks. The primary outcome was a change in the score on the Cohen-Mansfield Agitation Inventory (CMAI) (on a scale of 29 to 203, with higher scores indicating more agitation) at 12 weeks. RESULTS: There was no significant difference between the effects of donepezil and those of placebo on the basis of the change in CMAI scores from baseline to 12 weeks (estimated mean difference in change [the value for donepezil minus that for placebo], -0.06; 95% confidence interval [CI], -4.35 to 4.22). Twenty-two of 108 patients (20.4%) in the placebo group and 22 of 113 (19.5%) in the donepezil group had a reduction of 30% or greater in the CMAI score (the value for donepezil minus that for placebo, -0.9 percentage point; 95% CI, -11.4 to 9.6). There were also no significant differences between the placebo and donepezil groups in scores for the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change. CONCLUSIONS: In this 12-week trial, donepezil was not more effective than placebo in treating agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00142324 [ClinicalTrials.gov].).

Homocysteine as a predictor of cognitive decline in Alzheimer's disease.

OBJECTIVE: Moderately elevated levels of plasma total homocysteine are associated with an increased risk of developing Alzheimer's disease. We have tested whether baseline concentrations of homocysteine relate to the subsequent rate of cognitive decline in patients with established Alzheimer's disease (AD). METHODS: In 97 patients with AD, 73 pathologically-confirmed, we analysed the decline of global cognitive test scores (CAMCOG) over time from the first assessment for at least three 6-monthly visits up to a maximum of 9.5 years (in total 689 assessments). Non-linear mixed-effects statistical models were used. RESULTS: Baseline homocysteine levels showed a concentration-response relationship with the subsequent rate of decline in CAMCOG scores: the higher the homocysteine, the faster the decline. The relationship was significant in patients aged < 75 years who had not suffered a prior stroke. For example, in patients aged 65 years with a baseline homocysteine of 14 micromol/L, the decline from a CAMCOG score of 88 to a score of 44 occurred 19.2 (95% CI 6.8, 31.6) months earlier than in patients with a baseline homocysteine of 10 micromol/L. CONCLUSIONS: Raised homocysteine concentrations within the normal range among the elderly strongly relate to the rate of global cognitive decline in patients with Alzheimer disease. Plasma homocysteine can readily be lowered by B-vitamin treatment and trials should be carried out to see if such treatments can slow the rate of cognitive decline in relatively young patients with Alzheimer disease.

The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial.

BACKGROUND: Data from 12-week placebo-controlled trials have led to mounting concerns about increased mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotics; however, there are no mortality data from long-term placebo-controlled trials. We aimed to assess whether continued treatment with antipsychotics in people with AD is associated with an increased risk of mortality. METHODS: Between October, 2001, and December, 2004, patients with AD who resided in care facilities in the UK were enrolled into a randomised, placebo-controlled, parallel, two-group treatment discontinuation trial. Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months. An additional follow-up telephone assessment was done to establish whether each participant was still alive 24 months after the enrollment of the last participant (range 24-54 months). Causes of death were obtained from death certificates. Analysis was by intention to treat (ITT) and modified intention to treat (mITT). This trial is registered with the Cochrane Central Registry of Controlled Trials/National Research Register, number ISRCTN33368770. FINDINGS: 165 patients were randomised (83 to continue antipsychotic treatment and 82 to placebo), of whom 128 (78%) started treatment (64 continued with their treatment and 64 received placebo). There was a reduction in survival in the patients who continued to receive antipsychotics compared with those who received placebo. Cumulative probability of survival during the 12 months was 70% (95% CI 58-80%) in the continue treatment group versus 77% (64-85%) in the placebo group for the mITT population. Kaplan-Meier estimates of mortality for the whole study period showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (mITT log rank p=0.03; ITT p=0.02). The hazard ratio for the mITT group was 0.58 (95% CI 0.35 to 0.95) and 0.58 (0.36 to 0.92) for the ITT population. The more pronounced differences between groups during periods of follow up longer than 12 months were evident at specific timepoints (24-month survival 46%vs 71%; 36-month survival 30%vs 59%). INTERPRETATION: There is an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication; these results further highlight the need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in these patients. FUNDING: UK Alzheimer's Research Trust.

Brief psychosocial therapy for the treatment of agitation in Alzheimer disease (the CALM-AD trial).

BACKGROUND: Good practice guidelines state that a psychological intervention should usually precede pharmacotherapy, but there are no data evaluating the feasibility of psychological interventions used in this way. METHODS: At the first stage of a randomized blinded placebo-controlled trial, 318 patients with Alzheimer disease (AD) with clinically significant agitated behavior were treated in an open design with a psychological intervention (brief psychosocial therapy [BPST]) for 4 weeks, preceding randomization to pharmacotherapy. The therapy involved social interaction, personalized music, or removal of environmental triggers. RESULTS: Overall, 318 patients with AD completed BPST with an improvement of 5.6 points on the total Cohen-Mansfield Agitation Inventory (CMAI; mean [SD], 63.3 [16.0] to 57.7 [18.4], t = 4.8, df = 317, p < 0.0001). Therapy worksheets were completed in six of the eight centers, with the key elements of the intervention delivered according to the manual for >95% of patients. More detailed evaluation of outcome was completed for the 198 patients with AD from these centers, who experienced a mean improvement of 6.6 points on the total CMAI (mean [SD], 62.2 [14.3] to 55.6 [15.8], t = 6.5, df = 197, p < 0.0001). Overall, 43% of participants achieved a 30% improvement in their level of agitation. CONCLUSION: The specific attributable benefits of BPST cannot be determined from an open trial. However, the BPST therapy was feasible and was successfully delivered according to an operationalized manual. The encouraging outcome indicates the need for a randomized controlled trial of BPST.

A pilot randomised controlled trial of a brief cognitive behavioural group intervention to reduce recurrence rates in late life depression.

OBJECTIVES: To standardise the delivery of a brief group cognitive behaviour therapy intervention (CBT-G). To apply the intervention in a research setting and to estimate its effect on recurrence rates in recently depressed older adults, in preparation for a definitive study. METHOD: A CBT-G therapy manual was produced and the Cognitive Therapy Rating Scale (CTS-R) modified to assess therapy delivery. Forty-five adults aged 60 and over who had met ICD-10 criteria for major depression in the previous year and were still taking antidepressant medication were randomly allocated to CBT-G/antidepressant combination or antidepressant alone. Depression severity was measured at baseline, randomisation and 6 and 12 months after start of CBT-G using the Montgomery Asberg Rating Scale for Depression (MADRS). RESULTS AND CONCLUSION: One-year recurrence rates on the MADRS were encouragingly lower in participants receiving CBT-G [5/18 (27.8%)] compared with controls [8/18 (44.4%)] although this did not achieve statistical significance (adjusted RR 0.70 [95% CI 0.26-1.94]). In contrast, overall scores on the secondary outcome measure, the Beck Depression Inventory, increased in participants receiving CBT-G. The CBT-G manual was successfully implemented and therapy delivery achieved an overall satisfactory level of competence. We believe that evaluation of this promising intervention in a full-scale trial is warranted.

A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial).

BACKGROUND: There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease. DESIGN: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial. SETTING: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom. PARTICIPANTS: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo. INTERVENTIONS: Continue neuroleptic treatment for 12 mo or switch to an identical placebo. OUTCOME MEASURES: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI). RESULTS: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) -0.4 (95% confidence interval [CI] -6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) -2.4 (95% CI -8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI >/= 15 benefited on neuropsychiatric symptoms from continuing treatment. CONCLUSIONS: For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy. TRIAL REGISTRATION: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).

Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies.

OBJECTIVE: This investigation was undertaken to clarify the neuropathological substrates of key psychiatric symptoms in dementia with Lewy bodies. METHOD: The authors studied 112 autopsy-confirmed cases of dementia with Lewy bodies in patients who had had annual standardized clinical evaluations until their death. The relationships of persistent psychiatric symptoms (visual hallucinations, delusions, depression) to plaques (Consortium to Establish a Registry for Alzheimer's Disease protocol), tangles (Braak staging), and Lewy bodies (consensus Lewy body staging) were evaluated. In addition, symptom frequency and persistent symptoms were compared in the patients with Lewy body dementia and 90 patients with autopsy-confirmed Alzheimer's disease studied prospectively during life. RESULTS: The main neuropathological correlate of persistent visual hallucinations was the presence of less severe tangle pathology, but there was no significant association between tangle pathology and persistent delusions. Lewy body staging was associated with the presence of persistent visual hallucinations and persistent delusions. All baseline psychiatric features were significantly more frequent in dementia with Lewy bodies than in Alzheimer's disease, as were persistent visual hallucinations, but patients who had dementia with Lewy bodies and severe tangle pathology had a clinical symptom profile more similar to that of Alzheimer's disease patients and were less likely to have neocortical Lewy bodies. CONCLUSIONS: The modest proportion of patients with Lewy body dementia and more severe tangle pathology resembled Alzheimer's disease patients clinically. Unlike Alzheimer's disease, dementia with Lewy bodies showed a significant inverse association between tangle burden and psychosis.

A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome.

BACKGROUND: Although few placebo-controlled neuroleptic discontinuation studies have been conducted in people with dementia, such studies are essential to inform key clinical decisions. METHOD: A 3-month, double-blind, placebo-controlled, neuroleptic discontinuation study (June 2000 to June 2002) was completed in 100 care-facility residents with probable or possible Alzheimer's disease (according to National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria) who had no severe behavioral disturbances and had been taking neuroleptics for longer than 3 months. The Neuropsychiatric Inventory (NPI) was used to measure changes in behavioral and psychiatric symptoms. Quality of life was evaluated using Dementia Care Mapping. RESULTS: Eighty-two patients completed the 1-month assessment (36 placebo, 46 active). The number of participants withdrawing overall (N = 14 [30%] placebo, N = 14 [26%] active treatment) and because of exacerbation of behavioral symptoms (N = 6 [13%] placebo, N = 5 [9%] active treatment) was similar in the neuroleptic- and placebo-treated patients. As hypothesized, patients with baseline NPI scores at or below the median (< or = 14) had a particularly good outcome, with a significantly greater reduction of agitation in the patients receiving placebo (Mann-Whitney U test, z = 2.4, p =.018), while patients with higher baseline NPI scores were significantly more likely to develop marked behavioral problems if discontinued from neuroleptics (chi(2) = 6.8, p =.009). There was no overall difference in the change of quality of life parameters between groups. DISCUSSION: A standardized evaluation with an instrument such as the NPI may be a clinical indicator of which people with dementia are likely to benefit from discontinuation of neuroleptic treatment.

The grief experiences and needs of bereaved relatives and friends of older people dying through suicide: a descriptive and case-control study.

BACKGROUND: Little is known about grief experiences of individuals bereaved through suicide of older people. Legal procedures may be one source of distress. Studies have suggested that guilt feelings, and a sense of rejection, shame or stigma, are probably more frequent in relatives bereaved through suicide than in those bereaved through other modes of death. METHODS: We examined (a) problems experienced during legal procedures after death and (b) grief experiences, in 85 relatives and friends bereaved through the suicide of person 60 years old or over. In a case-control study the bereavement reactions in a subgroup of 46 people were compared with those of a control group bereaved by the natural death of an older person. Interviews, carried out 6-21 months after the deaths, included a semi-structured assessment of problems following the death, the Grief Experience Questionnaire (GEQ) and the Montgomery and Asberg Depression Rating Scale (MADRS). RESULTS: Thirty-six (42.4%) of those bereaved through suicide reported problems in their dealings with the coroner's office, and 33 (38.8%) described distress caused by media reporting of the inquest. Depression scores were similar in the group of individuals bereaved through suicide and those bereaved through natural causes. The former scored higher on subscales of the GEQ measuring stigmatisation, shame, sense of rejection and "unique reactions" compared with those bereaved through natural death. LIMITATIONS: The participation rate of potential subjects was somewhat low, especially in the control group. Proportions of different kinships to the deceased differed in the study and control groups. CONCLUSIONS: Problems in the media reporting of coroners' inquests and in inquest procedures are a frequent source of distress for bereaved relatives. The common themes of stigma, shame, and sense of rejection in bereavement after suicide suggest that these areas should be specifically addressed in the counselling of relatives bereaved in this way.

Do general practitioners believe that their older patients physical symptoms are somatized?

OBJECTIVE: To establish general practitioner (GP) ratings of the origins of their older patients' physical symptoms, and to test the hypothesis that those older patients rated as somatizing would have similar clinical characteristics to those found in studies of younger attenders. METHODS: A prospective study among older primary care attenders in two UK practices. All were rated for psychiatric disorder, physical illness, frequency of attendance and demographics. GPs rated degree of somatization on a 5-point scale. RESULTS: Almost three quarters of attenders were considered to have some psychological component to physical presentations, with 13.3% rated as primarily or entirely psychological. Frequent attendance, female gender and antidepressant prescription were associated with high somatization ratings, but depressive disorder was not. CONCLUSION: GPs consider somatization to be an important cause of physical presentations among older patients, especially among female frequent attenders.

Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial.

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.