John Grimley Evans

Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people

BACKGROUNDnFolate deficiency can result in congenital neural tube defects and megaloblastic anaemia. Low folate levels may be due to insufficient dietary intake or inefficient absorption, but impaired metabolic utilization also occurs.Because B12 deficiency can produce a similar anaemia to folate deficiency, there is a risk that folate supplementation can delay the diagnosis of B12 deficiency, which can cause irreversible neurological damage. Folic acid supplements may sometimes therefore include vitamin B12 supplements with simultaneous administration of vitamin B12.Lesser degrees of folate inadequacy are associated with high blood levels of the amino acid homocysteine which has been linked with the risk of arterial disease, dementia and Alzheimers disease. There is therefore interest in whether dietary supplementation can improve cognitive function in the elderly.However, any apparent benefit from folic acid which was given in combination with B12 needs to be corrected for any effect of vitamin B12 alone. A separate Cochrane review of vitamin B12 and cognitive function has therefore been published.nnnOBJECTIVESnTo examine the effects of folic acid supplementation, with or without vitamin B12, on elderly healthy or demented people, in preventing cognitive impairment or retarding its progress.nnnSEARCH STRATEGYnTrials were identified from a search of the Cochrane Dementia and Cognitive Improvement Groups Specialized Register on 10 October 2007 using the terms: folic acid, folate, vitamin B9, leucovorin, methyltetrahydrofolate, vitamin B12, cobalamin and cyanocobalamin. This Register contains references from all major health care databases and many ongoing trials databases. In addition MEDLINE, EMBASE, CINAHL, PsychINFO and LILACS were searched (years 2003-2007) for additional trials of folate with or without vitamin B12 on healthy elderly people.nnnSELECTION CRITERIAnAll double-blind, placebo-controlled, randomized trials, in which supplements of folic acid with or without vitamin B12 were compared with placebo for elderly healthy people or people with any type of dementia or cognitive impairment.nnnDATA COLLECTION AND ANALYSISnThe reviewers independently applied the selection criteria and assessed study quality. One reviewer extracted and analysed the data. In comparing intervention with placebo, weighted mean differences and standardized mean difference or odds ratios were estimated.nnnMAIN RESULTSnEight randomized controlled trials fulfilled the inclusion criteria for this review. Four trials enrolled healthy older people, and four recruited participants with mild to moderate cognitive impairment or dementia with or without diagnosed folate deficiency. Pooling the data was not possible owing to heterogeneity in sample selections, outcomes, trial duration, and dosage. Two studies involved a combination of folic acid and vitamin B12.There is no adequate evidence of benefit from folic acid supplementation with or without vitamin B12 on cognitive function and mood of unselected healthy elderly people. However, in one trial enrolling a selected group of healthy elderly people with high homocysteine levels, 800 mcg/day folic acid supplementation over three years was associated with significant benefit in terms of global functioning (WMD 0.05, 95% CI 0.004 to 0.096, P = 0.033); memory storage (WMD 0.14, 95% CI 0.04 to 0.24, P = 0.006) and information-processing speed (WMD 0.09, 95% CI 0.02 to 0.16, P = 0.016).Four trials involved people with cognitive impairment. In one pilot trial enrolling people with Alzheimers disease, the overall response to cholinesterase inhibitors significantly improved with folic acid at a dose of 1mg/day (odds ratio: 4.06, 95% CI 1.22 to 13.53; P = 0.02) and there was a significant improvement in scores on the Instrumental Activities of Daily Living and the Social Behaviour subscale of the Nurses Observation Scale for Geriatric Patients (WMD 4.01, 95% CI 0.50 to 7.52, P = 0.02). Other trials involving people with cognitive impairment did not show any benefit in measures of cognitive function from folic acid, with or without vitamin B12.Folic acid plus vitamin B12 was effective in reducing serum homocysteine concentrations (WMD -5.90, 95% CI -8.43 to -3.37, P < 0.00001). Folic acid was well tolerated and no adverse effects were reported.nnnAUTHORS CONCLUSIONSnThe small number of studies which have been done provide no consistent evidence either way that folic acid, with or without vitamin B12, has a beneficial effect on cognitive function of unselected healthy or cognitively impaired older people. In a preliminary study, folic acid was associated with improvement in the response of people with Alzheimers disease to cholinesterase inhibitors. In another, long-term use appeared to improve the cognitive function of healthy older people with high homocysteine levels. More studies are needed on this important issue.

Folic acid with or without vitamin B12 for cognition and dementia.

BACKGROUNDnFolates are vitamins essential to the development of the central nervous system. Insufficient folate activity at the time of conception and early pregnancy can result in congenital neural tube defects. In adult life folate deficiency has been known for decades to produce a characteristic form of anaemia (megaloblastic). More recently degrees of folate inadequacy, not severe enough to produce anaemia, have been found to be associated with high blood levels of the amino acid homocysteine. Such degrees of folate inadequacy can arise because of insufficient folates in the diet or because of inefficient absorption or metabolic utilisation of folates due to genetic variations. Conventional criteria for diagnosing folate deficiency may be inadequate for identifying people capable of benefiting from dietary supplementation. High blood levels of homocysteine have been linked with the risk of arterial disease, dementia and Alzheimers disease. There is therefore interest in whether dietary supplements of folic acid (an artificial chemical analogue of naturally occurring folates) can improve cognitive function of people at risk of cognitive decline associated with ageing or dementia, whether by affecting homocysteine metabolism or through other mechanisms. There is a risk that if folic acid is given to people who have undiagnosed deficiency of vitamin B12 it may lead to neurological damage. Vitamin B12 deficiency produces both an anaemia identical to that of folate deficiency but also causes irreversible damage to the central and peripheral nervous systems. Folic acid will correct the anaemia of vitamin B12 deficiency and so delay diagnosis but will not prevent progression to neurological damage. For this reason trials of folic acid supplements may involve simultaneous administration of vitamin B12. Apparent benefit from folic acid given in the combination would therefore need to be corrected for any effect of vitamin B12 alone. A separate Cochrane review of vitamin B12 and cognitive function is being prepared.nnnOBJECTIVESnTo examine the effects of folic acid supplementation, with or without vitamin B12, on elderly healthy and demented people, in preventing cognitive impairment or retarding its progress.nnnSEARCH STRATEGYnTrials were identified from a search of the Cochrane Dementia and Cognitive Improvement Specialized Register Group on 9 April 2003 using the terms: folic acid, folate, vitamin B9, leucovorin, methyltetrahydrofolate, vitamin B12, cobalamin, cyanocobalamin, dementia, cognitive function, cognitive impairment, Alzheimers disease, vascular dementia, mixed dementia and controlled trials. MEDLINE and EMBASE (both all years) were searched for additional trials on healthy people.nnnSELECTION CRITERIAnAll double-blind placebo-controlled randomized trials, in which supplements of folic acid with or without vitamin B12 were compared with placebo for elderly healthy people or people with any type of dementia or cognitive impairment.nnnDATA COLLECTION AND ANALYSISnThe reviewers independently applied the selection criteria and assessed study quality. One reviewer extracted and analysed the data. In comparing intervention with placebo, weighted mean differences, and standardized mean difference or odds ratios were estimated.nnnMAIN RESULTSnFour randomized controlled trials fulfilled the inclusion criteria for this review. One trial (Bryan 2002) enrolled healthy women, and three (Fioravanti 1997; Sommer 1998; VITAL 2003) recruited people with mild to moderate cognitive impairment or dementia with or without diagnosed folate deficiency. Fioravanti 1997 enrolled people with mild to moderate cognitive impairment or dementia as judged by scores on the Mini-Mental State Examination (MMSE) and Global Deterioration Scale and with serum folate level<3ng/l. One trial (VITAL 2003) studied the effects of a combination of vitamin B12 and folic acid on patients with mild to moderate cognitive impairment due to Alzheimers disease or mixed dementia. The analysis from the included trials found no benefit from folic acid with or without vitamin B12 in comparison with placebo on any measures of cognition and mood for healthy or cognitively impaired or demented people: Folic acid effect and healthy participants: there was no benefit from of oral 750 mcg folic acid per day for five weeks compared with placebo on measures of cognition and mood of 19 healthy women aged 65 to 92. Folic acid effect and people with mild to moderate cognitive decline or dementia: there were no statistically significant results in favour of folic acid with or without vitamin B12 on any measures of cognitive function. Scores on the Mini-Mental State Examination (MMSE) revealed no statistically significant benefit from 2 mg per day folic acid plus 1mg vitamin B12 for 12 weeks when compared with placebo (WMD 0.39, 95% CI -0.43 to 1.21, P=0.35). Cognitive scores on the Alzheimers Disease Scale (ADAS-Cog) showed no statistically significant benefit from 2 mg /day folic acid plus 1 mg /day vitamin B12 for 12 weeks compared with placebo (WMD 0.41, 95% -1.25 to 2.07, P=4.63). The Bristol Activities of Daily Living Scale (BADL) revealed no benefit from 2mg per day of folic acid plus 1 mg vitamin B12 for 12 weeks in comparison with placebo (WMD -0.57, 95%CI -1.95 to 0.81, P=0.42). None of the sub tests of the Randt Memory Test (RMT) showed statistically significant benefit from 15 mg of folic acid orally per day for 9 weeks when compared with placebo. One trial (Sommer 1998) reported a significant decline compared with placebo in two cognitive function tasks in demented patients who had received high doses of folic acid (10 mg /day) for unspecified periods. One trial (VITAL 2003) showed that 2 mg folic acid plus 1 mg vitamin B12 daily for 12 weeks significantly lowered serum homocysteine concentrations (P <0.0001).nnnREVIEWERS CONCLUSIONSnThere was no beneficial effect of 750 mcg of folic acid per day on measures of cognition or mood in older healthy women. In patients with mild to moderate cognitive decline and different forms of dementia there was no benefit from folic acid on measures of cognition or mood. Folic acid plus vitamin B12 was effective in reducing the serum homocysteine concentrations. Folic acid was well tolerated and no adverse effects were reported. More studies are needed.

Vitamin B6 for cognition

Background nMicronutrient status can affect cognitive function at all ages. Vitamin deficiencies could influence memory function and might contribute to age-associated cognitive impairment and dementia. Vitamin B6, comprising three chemically distinct compounds, pyridoxal, pyridoxamine, and pyridoxine, is involved in the regulation of mental function and mood. Vitamin B6 is also an essential homocysteine re-methylation cofactor, and deficiency is associated with an increase in blood homocysteine levels. Homocysteine is a risk factor for cerebrovascular disease and may also have directly toxic effects on neurons of the central nervous system. Neuropsychiatric disorders including seizures, migraine, chronic pain and depression have been linked to vitamin B6 deficiency. Epidemiological studies indicate that poor vitamin B6 status is common among older people. Hyperhomocysteinaemia has been suggested as a cause or mechanism in the development Alzheimers disease and other forms of dementia. Supplementation with B vitamins including vitamin B6 has been shown to reduce blood homocysteine levels. n nObjectives nTo assess the efficacy of vitamin B6 supplementation in reducing the risk of developing cognitive impairment by older healthy people, or improving cognitive functioning of people with cognitive decline and dementia, whether or not vitamin B6 deficiency has been diagnosed. n nSearch methods nThe Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 16 March 2008 using the terms: B6, B 6, B-6, pyridoxine, pyridoxamine, pyridoxal. The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources. n nSelection criteria nAll unconfounded, double-blind randomized controlled trials in which the intervention with vitamin B6 was compared with placebo for healthy older people or people with cognitive decline or dementia. The primary outcome of interest was the efficacy of vitamin B6 supplementation on cognitive function. n nData collection and analysis nThe two reviewers independently evaluated all studies identified as possibly meeting the criteria for inclusion. One reviewer independently extracted the data. Studies were rated for their overall quality. The weighted mean differences between treatment and placebo groups, with 95% confidence intervals, were calculated for each outcome. Review Manager version 4.2 was used to analyse the variance. n nMain results nNo trials of vitamin B6 involving people with cognitive impairment or dementia were found. n nThe two trials included in the review (Bryan 2002; Deijen 1992) used a double-blind, randomized, placebo-controlled design and involved 109 healthy older people. One trial restricted enrolment to women and the other to men. n nVitamin B6 supplementation and healthy older women: n nBryan 2002, enrolled 211 healthy women from various age groups into a five-week study. The trial was of multifactorial design with folic acid, vitamin B12, vitamin B6 and placebo in its four arms. Twelve healthy women aged 65 to 92 years received 75 mg vitamin B6 orally per day and were compared with 21 healthy women who were allocated to placebo. No statistically significant benefits from vitamin B6 on mood or cognition were observed. n nVitamin B6 supplementation and healthy older men: n nDeijen 1992, recruited 76 healthy men aged 70 to 79 years. They were divided into 38 matched pairs, one member of each pair randomly allocated to 20 mg of vitamin B6 (pyridoxine hydrochloride) per day for 12 weeks the other to placebo. No statistically significant differences between treatment and placebo were found in their effects on cognition or mood. n nEffect of vitamin B6 supplementation on vitamin B6 status: n nDeijen 1992, reported that 20 mg of pyridoxine hydrochloride per day for 12 weeks increased blood vitamin B6 activity as assessed as by plasma pyridoxal-5-phosphate (WMD 238, 95%CI 211.58 to 264.42, P<0.00001) and erythrocyte enzyme asparate aminotransferase (WMD 0.43, 95%CI 0.30 to 0.56, P<0.00001) n nEffect of vitamin B6 supplementation on blood homocysteine concentration: n nNeither of the included trials measured homocysteine levels. n nDrop-outs: n nAll participants allocated to vitamin B6 or placebo completed the trial protocol. n nAdverse events: n nNo adverse effects were reported. n nEffect of vitamin B6 on carer burden, care costs and institutionalization rate: n nWe found no trials in which these outcomes were assessed. n nAuthors conclusions nThis review found no evidence for short-term benefit from vitamin B6 in improving mood (depression, fatigue and tension symptoms) or cognitive functions. For the older people included in one of the two trials included in the review, oral vitamin B6 supplements improved biochemical indices of vitamin B6 status, but potential effects on blood homocysteine levels were not assessed in either study. n nThis review found evidence that there is scope for increasing some biochemical indices of vitamin B6 status among older people. More randomized controlled trials are needed to explore possible benefits from vitamin B6 supplementation for healthy older people and for those with cognitive impairment or dementia.

The ACE gene and Alzheimer's disease susceptibility

A recent study suggested that the insertion (I) allele in intron 16 of the angiotensin converting enzyme gene (ACE) is associated with Alzheimers disease (AD) risk. In our series of 239 necropsy confirmed late onset AD cases and 342 elderly non-demented controls aged >73 years, we found significantly different ACE genotype distributions in the case and control groups (p=0.007). Homozygotes for both the I and D alleles were associated with a higher risk compared to DI heterozygotes. While the APOEε4 allele was strongly associated with AD risk in our series, we found no evidence for an interaction between the APOE andACE loci. In addition, no interactions were observed between ACE and gender or age at death of the AD cases. A meta-analysis of all published reports (12 case-control series in total) suggested that both the II and IDACE genotypes are associated with increased AD risk (odds ratio (OR) for II v DD 1.36, 95% confidence interval (CI)=1.13-1.63, OR for DIv DD 1.33, 95% CI=1.14-1.53, p=0.0002).

Evidence-based pharmacotherapy of Alzheimer's disease

Dementia is an acquired global impairment of cognitive capacities. Approximately 5% of people aged over 65 yr are affected by dementia, and some 70% of cases are thought to be due primarily to Alzheimers disease. Descriptions of the clinical manifestations of Alzheimers disease have been increasingly refined in the last decade but there is no diagnostic test for what remains fundamentally a pathologically defined condition. At the present time interventions for Alzheimers disease are limited to those that modify the manifestations of the disease, and foremost amongst the candidates available are the cholinesterase inhibitors. The rationale for the use of cholinergic drugs for Alzheimers disease lies in enhancing the secretion of, or prolonging the half-life of, acetylcholine in the brain. Several potential compounds have been tested, but short half-lives and a high incidence of cholinergic and other adverse effects have eliminated most. Only three are widely licensed for use, donepezil, galantamine and rivastigmine. Their efficacy is relatively modest. These drugs have been tested in 32 randomized, placebo-controlled trials. The trials assess cognitive function primarily, and in addition they may assess global function, activities of daily living, quality of life and behavioural disturbance typically over 3 or 6 months. The performance of each drug is summarized in a Cochrane review, a systematic review carried out according to strict guidelines. There was a significant benefit in favour of treatment compared with placebo for cognition and activities of daily living, but withdrawals due to adverse events were significantly higher for treatment than placebo for all three drugs. There is little evidence from direct comparisons between the three drugs. There are several economic analyses of the cost-effectiveness of these drugs, but the findings cannot be considered robust owing to inadequate data. A range of other pharmacological treatments have been tested, including selegiline, piracetam, vitamin E, Ginkgo biloba, anti-inflammatory drugs and hormone replacement therapy, but, so far, Cochrane reviews have not established the efficacy of these interventions for Alzheimers disease. A Cochrane review of memantine shows benefits on cognitive and global function of the same order of magnitude as seen for the cholinesterase inhibitors. Memantine has been licensed in Europe for treatment of patients with moderately severe to severe Alzheimers disease.

Piracetam for dementia or cognitive impairment

OBJECTIVESnTo determine the clinical efficacy of piracetam for the features of dementia or cognitive impairment, classified according to the major subtypes of dementia: vascular, Alzheimers disease or mixed vascular and Alzheimers disease or unclassified dementia or cognitive impairment not fulfilling the criteria for dementia.nnnSEARCH STRATEGYnThe Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials was searched using the terms piracetam, nootropic and 2-oxo-l-pyrrolidine acetamide. Electronic bibliographic databases including Medline, Embase, PychLit, Current Contents, Sociofile were searched back to 1966 with the terms piracetam, nootropics, 2-oxo-1-pyrrolidine and trials. In addition the pharmaceutical company responsible for marketing most of the piracetam worldwide, UCB Pharma, provided a comprehensive list of abstracts, which included many unpublished studies. As many of these unpublished, placebo control studies will be reviewed as possible.nnnSELECTION CRITERIAnAll unconfounded trials specified as randomised in which treatment with piracetam was administered for more than a day and compared with placebo in patients with dementia of the Alzheimers type, vascular dementia or mixed vascular and Alzheimers disease or uncalssified dementia or cognitive impairment not fulfilling the criteria for dementia.nnnDATA COLLECTION AND ANALYSISnData were extracted independently by two reviewers. Each study was independently verified as fulfilling the inclusion criteria. Studies were rated for methodological quality by assessment of blinding and loss before analysis as described by Jadad et al. (1996). Studies were pooled if appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used. Sensitivity analyses were performed to determine if successive elimination of those studies performing most poorly on these quality criteria changed the effect estimate.nnnMAIN RESULTSnUnfortunately, many of these studies were crossover in design and data were unavailable from the first period. In many other studies data were not able to be extracted from the first period. From the data that were pooled there was only one outcome where significant amounts of evidence were available, Global Impression of Change. There was evidence of heterogeneity in the results from the individual studies, Chi squared test = 20.8 (df=5). Using a fixed effects model the odds ratio for improvement in the Piracetem group compared with the Placebo group was 3.55, [95% CI][2.45, 5.16]. If a random effects model was used the odds ratio was 3.47 [1.29, 9.30]. If one single-blind study was excluded, the fixed effects model yielded an odds ratio of 3.36 [2.29, 4.99] and if a random effects model was applied then the odds ratio was 2.89 [1.01, 8.24]. The evidence of effects on cognition and other measures, was inconclusive.nnnREVIEWERS CONCLUSIONSnAt this stage the evidence available from the published literature does not support the use of Piracetem in the treatment of people with dementia or cognitive impairment because effects were found only on global impression of change but not on any of the more specific measures. There is a need for further evaluation of piracetam by : 1) Obtaining the data from these studies for an individual patient database review, 2) Performing a randomised trial of Piracetam in patients with diagnoses made by currently accepted diagnostic criteria. Piracetam should be trialled for a period of at least 6 months and preferably longer. Specific cognitive instruments which are sensitive to change, Clinician Global Impression of Change, levels of dependency and caregiver quality of life scales should also be incorporated in such a study.

Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people

BACKGROUNDnIn view of the theoretical possibility of beneficial effects of DHEA or DHEAS in retarding age-associated deterioration in cognitive function, we have reviewed studies in this area.nnnOBJECTIVESnTo establish whether administration of DHEA, or its sulphate, DHEAS, improves cognitive function or reduces the rate of decline of cognitive function in normal older adults.nnnSEARCH STRATEGYnTrials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 10 October 2005 using the terms dhea*, prasterone, dehydroepiandrosterone*. In addition MEDLINE, EMBASE, PsycINFO and CINAHL were searched to find trials with volunteers who had no or minor memory complaints. Relevant journals, personal communications and conference abstracts were searched for randomized controlled trials investigating the effects of DHEA/S on cognition in older adults.nnnSELECTION CRITERIAnAll randomized placebo-controlled trials enrolling people aged over 50 without dementia and to whom DHEA/S in any dosage was administered for more than one day were considered for inclusion in the review.nnnDATA COLLECTION AND ANALYSISnData for the specified outcomes were independently extracted by two reviewers (JGE and RM) and cross-checked. Any discrepancies were discussed and resolved. No data pooling was undertaken owing to the lack of availability of the relevant statistics.nnnMAIN RESULTSnOnly three studies provided results from adequate parallel-group data. Barnhart 1999 enrolled perimenopausal women with complaints of decreased well-being and, using three cognitive measures, found no significant effect of DHEA compared with placebo at 3 months. Wolf 1998b enrolled 75 healthy volunteers (37 women and 38 men aged 59-81) in a study of the effect of DHEA supplements on cognitive impairment induced by stress; after two weeks of treatment, placebo group performance deteriorated significantly on a test of selective attention following a psychosocial stressor (p<0.05), while deterioration was not evident in the DHEA group (p=0.85). However, when compared with placebo, DHEA was associated with a significant impairment on a visual memory recall test (p<0.01) following the stressor. No significant effects were found on a third cognitive task. Effects were not found on tasks when administered in the absence of a stressor. van Niekerk 2001 found no effect on cognitive function in 46 men aged 62-76 from three months of DHEA supplementation. DHEA supplements were well tolerated and without significant adverse effects apart from the reduced performance in the visual memory recall test observed in one trial.nnnAUTHORS CONCLUSIONSnWhat little evidence there is from controlled trials does not support a beneficial effect of DHEA supplementation on cognitive function of non demented middle-aged or elderly people. There is no consistent evidence from the controlled trials that DHEA produces any adverse effects. In view of growing public enthusiasm for DHEA supplementation, particularly in the USA, and the theoretical possibility of long-term neuroprotective effects of DHEA/S, there is a need for further high quality trials in which the duration of DHEA treatment is longer than one year, and the number of participants is large enough to provide adequate statistical power.

Subjective barriers to prevent wandering of cognitively impaired people

BACKGROUNDnPeople with dementia often wander, at times putting themselves at risk and presenting challenges to carers and institutional staff. Traditional interventions to prevent wandering include restraint, drugs and locked doors. Cognitively impaired people may respond to environmental stimuli (sounds, images, smells) in ways distinct from healthy people. This has led to trials of visual and other selective barriers (such as mirrors, camouflage, grids/stripes of tape) that may reduce wandering.nnnOBJECTIVESnWe assess the effect of subjective exit modifications on the wandering behaviour of cognitively impaired people. The second objective is to inform the direction and methods of future research.nnnSEARCH STRATEGYnThe search strategy includes electronic searches of relevant bibliographic and trials databases, citation indices and relevant medical journals.nnnSELECTION CRITERIAnRandomized controlled trials and controlled trials provide the highest quality evidence, but interrupted time series are also considered as they may contribute useful information. Participants are people with dementia or cognitive impairment who wander, of any age, and in any care environment - hospital, other institution, or their own home. Interventions comprise exit modifications that aim to function as subjective barriers to prevent the wandering of cognitively impaired people. Locks, physical restraints, electronic tagging and other types of barrier are not included.nnnDATA COLLECTION AND ANALYSISnThe criteria for inclusion or exclusion of studies are applied independently by two reviewers. All outcomes that are meaningful to people making decisions about the care of wanderers are recorded. These include the number of exits or carer interventions, resource use, acceptability of the intervention and the effects on carer and wanderer anxiety or distress. heterogeneity of clinical area, of study design and of intervention was substantial.nnnMAIN RESULTSnNo randomized controlled or controlled trials were found. The other experimental studies that we identified were unsatisfactory. Most were vulnerable to bias, particularly performance bias; most did not classify patients according to type or severity of dementia; in all studies, outcomes were measured only in terms of wandering frequency rather than more broadly in terms of quality of life, resource use, anxiety and distress; no studies included patients with delirium; no studies were based in patients homes.nnnREVIEWERS CONCLUSIONSnThere is no evidence that subjective barriers prevent wandering in cognitively impaired people.

Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK

Concerns about risks for older people with vitamin B12 deficiency have delayed the introduction of mandatory folic acid fortification in the UK. We examined the risks of anaemia and cognitive impairment in older people with low B12 and high folate status in the setting of voluntary fortification in the UK. Data were obtained from two cross-sectional studies (n 2403) conducted in Oxford city and Banbury in 1995 and 2003, respectively. Associations (OR and 95 % CI) of cognitive impairment and of anaemia with low B12 status (holotranscobalamin < 45 pmol/l) with or without high folate status (defined either as serum folate >30 nmol/l or >60 nmol/l) were estimated after adjustment for age, sex, smoking and study. Mean serum folate levels increased from 15.8 (sd 14.7) nmol/l in 1995 to 31.1 (sd 26.2) nmol/l in 2003. Serum folate levels were greater than 30 nmol/l in 9 % and greater than 60 nmol/l in 5 %. The association of cognitive impairment with low B12 status was unaffected by high v. low folate status (>30 nmol/l) (OR 1.50 (95 % CI 0.91, 2.46) v. 1.45 (95 % CI 1.19, 1.76)), respectively. The associations of cognitive impairment with low B12 status were also similar using the higher cut-off point of 60 nmol/l for folate status ((OR 2.46; 95 % CI 0.90, 6.71) v. (1.56; 95 % CI 1.30, 1.88)). There was no evidence of modification by high folate status of the associations of low B12 with anaemia or cognitive impairment in the setting of voluntary fortification, but periodic surveys are needed to monitor fortification.

Trazodone for agitation in dementia

BACKGROUNDnBehavioural and psychiatric disturbances affect at least 50% of people with Alzheimers disease and other dementias. Neuroleptic drugs are extensively prescribed to treat behavioural manifestations of dementia in spite of only modest efficacy and a high frequency of adverse effects. There is clearly a need for safer and more effective remedies. Trazodone is a psychoactive compound with sedative and antidepressant properties, and with mixed serotonin agonist and antagonist effects. Functional serotonergic deficits may be related to the genesis of behavioural disturbances in dementia.nnnOBJECTIVESnTo determine the clinical efficacy and safety of trazodone, for any type of behavioural or psychological cognition in people with dementia without an additional diagnosis of depression.nnnSEARCH STRATEGYnTrials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 1 June 2004 using the terms trazodon*, beneficat, desirel, sideril, trazodil, trazalon. This register contains records from all major health care databases and many ongoing trials databases, and is updated regularly.nnnSELECTION CRITERIAnAll unconfounded, double-blind, randomised controlled trials, comparing trazodone with placebo in managing behavioural and psychiatric symptoms (except depression) in any type of dementia.nnnDATA COLLECTION AND ANALYSISnAvailable data for this analysis were extracted from the two included studies and odds ratios or average differences, with 95% confidence intervals, calculated. Intention-to-treat analysis was undertaken where possible.nnnMAIN RESULTSnTwo studies were included, comprising 104 participants with dementia. The trials differed in design - one being a parallel-group study of patients with Alzheimers disease (Teri 2000) and one being a cross-over study of patients with frontotemporal dementia (Lebert 2004). It was not possible to pool the data. The studies were respectively of 16 and 6 weeks duration, using trazodone from 50 to 300mg daily. Both trials examined global clinical state, behavioural disturbances and cognitive function. Teri 2000 also assessed activities of daily living and caregiver burden. Compared with placebo, the use of trazodone was not associated with statistically significant benefits for behavioural manifestations as measured by various rating scales (ABID, CERAD-BRSD,CMAI, NPI). Analysis of changes from baseline for clinical impression of change and for cognitive function did not produce statistically significant results in favour of trazodone. A variety of adverse effects were recorded with no significant differences between trazodone and placebo.nnnREVIEWERS CONCLUSIONSnThere is insufficient evidence to recommend the use of trazodone as a treatment for behavioural and psychological manifestations of dementia. In order to assess effectiveness and safety of trazodone, longer-term trials are needed, involving larger samples of participants with a wider variety of types and severities of dementia.