Prevention of dementia: a role for B vitamins?

Dementia has reached epidemic proportions, with an estimated 4.6 million new cases worldwide each year. With an aging world population the prevalence of dementia will increase dramatically in the next few decades. Of the predicted 114 million who will have dementia in 2050 about three-quarters will live in the less-developed regions. Although strongly age -related, dementia is not an inevitable part of aging but is a true disease caused by exposure to several genetic and non-genetic risk factors. Prevention will be possible when the non genetic risk factors have been identified. Apart from age, more than 20 non-genetic risk factors have been postulated but very few have been established by randomised intervention studies. Elevated blood concentrations of total homocysteine and low-normal concentrations of B vitamins (folate, vitamins B-12 and B-6) are candidate risk factors for both Alzheimer's disease and vascular dementia. A review of the literature up to the end of 2005 shows the following. Seventy seven cross-sectional studies on > 34,000 subjects and 33 prospective studies on > 12,000 subjects have shown associations between cognitive deficit or dementia and homocysteine and/or B vitamins. Biologically plausible mechanisms have been proposed to account for these associations, including atrophy of the cerebral cortex, but a definite causal pathway has yet to be shown. Raised plasma total homocysteine is a strong prognostic marker of future cognitive decline, and is common in world populations. Low-normal concentrations of the B vitamins, the main determinant of homocysteine concentrations, are also common and occur in particularly vulnerable sections of the population, such as infants and the elderly. Large-scale randomised trials of homocysteine-lowering B vitamins are needed to see if a proportion of dementia in the world can be prevented.     

Is complexity of work associated with risk of dementia? The Canadian Study of Health And Aging

The authors evaluated the association of complexity of work with data, people, and things with the incidence of dementia, Alzheimer's disease, and vascular dementia in the Canadian Study of Health and Aging, while adjusting for work-related physical activity. The Canadian Study of Health and Aging is a 10-year population study, from 1991 to 2001, of a representative sample of persons aged 65 years or older. Lifetime job history allowed application of complexity scores and classification of work-related physical activity. Analyses included 3,557 subjects, of whom 400 were incident dementia cases, including 299 with Alzheimer's disease and 93 with vascular dementia. In fully adjusted Cox regression models, high complexity of work with people or things reduced risk of dementia (hazard ratios were 0.66 (95% confidence interval: 0.44, 0.98) and 0.72 (95% confidence interval: 0.52, 0.99), respectively) but not Alzheimer's disease. For vascular dementia, hazard ratios were 0.36 (95% confidence interval: 0.15, 0.90) for high complexity of work with people and 0.50 (95% confidence interval: 0.25, 1.00) for high complexity of work with things. Subgroup analyses according to median duration (23 years) of principal occupation showed that associations with complexity varied according to duration of employment. High complexity of work appears to be associated with risk of dementia, but effects may vary according to subtype.     

Effect of long-term treatment with galantamine on weight of patients with Alzheimer’s dementia

Objectives

There is discussion about the effect of cholinesterase inhibitors (CERs) on weight of patients with Alzheimer’s disease (AD). Given the adverse outcomes of weight loss in AD patients, it is important to establish the effect of CERs on weight. This study aimed tot assess the long-term effect of galantamine on weight of AD patients.

Design, setting and participants

This longitudinal study was performed at a large memory clinic in the North of the Netherlands. During the period 2002 to 2010, 303 communitydwelling AD patients, aged 65 years or older who started using a cholinesterase inhibitor (CER), were included.

Measurements

Socio-demographic characteristics and data on comorbidity, number of medications, type and dosage of CER, use of care, cognitive function, behaviour and nutritional status (weight, Body Mass Index (BMI)) were recorded at the time the diagnosis AD was made and at subsequent outpatient clinic visits. The Generalized Estimating Equations (GEE) model was used to determine the effect of galantamine of 16 mg and 24 mg on weight. The effect of galantamine in a dose of 16 and 24 mg was investigated because the other groups (rivastigmine, galantamine 8 mg) were too small to determine the effect on weight by GEE analysis. Donepezil is not available in the Netherlands.

Results

The median follow-up time between the moment patients started using a CER (T0) and the 1st visit was 6 months (n=300); between T0 and the 2nd visit 13 months (n=212); between T0 and the 3rd visit 25 months (n=117) and between T0 and the 4th visit 37 months (n=58). Galantamine 16 mg and 24 mg, corrected for age, gender, social status, informal care, professional care, comorbidity, number of medications, cognition, behaviour and appetite, had no effect on weight (p > 0.05). Male patients had a higher average weight compared to female patients (p=0.000, B=8.333). Patients without an informal caregiver (p=0.01, B=?3.697) or partner (p=0.042, B=?3.197) had a lower average weight compared to patients with an informal caregiver or partner.

Conclusion

Weight loss in AD patients should not be attributed to long-term treatment with galantamine. This is in accordance with the French guideline. If AD patients are losing weight, other causes, including insufficient care, should be investigated.     

‘How can they tell?’ A qualitative study of the views of younger people about their dementia and dementia care services

There is growing interest in eliciting the views of younger people with dementia (i.e. those under 65 years of age) within health and social care research. The often erroneous view that these individuals are not capable of expressing their views and experiences has now been seriously challenged. The present paper draws on the findings from 14 qualitative in-depth interviews with younger people with dementia conducted in the South-west of England, and considers some of the issues involved in interviewing people with dementia. Purposive and snowballing techniques were used to recruit participants. Data were transcribed and subjected to comparative textual analysis to index, code and analyse the data for emergent themes. Four major themes emerged: (1) the general experience of having dementia; (2) dementia diagnosis; (3) the importance of age; and (4) risk and danger issues. The results indicate that the majority of participants were articulate and insightful about their experiences and needs. The present paper concludes by arguing that the challenge for health and social care professionals is to engage with and consult such individuals about their experiences and what they want from dementia care services, and the authors consider some of the issues involved in interviewing people with dementia.     

Compassion in healthcare – lessons from a qualitative study of the end of life care of people with dementia

Objectives

A lack of compassion in UK healthcare settings has received much recent attention. This study explores the experiences of people with dementia in the last year of life and time surrounding death and how the presence and lack of compassion, kindness and humanity influenced the experience of care.

Design

Qualitative in-depth interviews with bereaved informal carers of people with dementia.

Setting

United Kingdom.

Participants

Forty bereaved carers – 31 women and nine men – with an age range of 18–86 years and from wide socioeconomic backgrounds participated.

Main outcome measures

Experiences of carers of care for person with dementia during last year of life.

Results

The interviews highlighted differences and challenges in care settings in providing compassionate, humanistic care and the impact of the care experienced by the person with dementia during the last year of life on informal carers during the bereavement period and beyond. Excellent examples of compassionate care were experienced alongside very poor and inhumane practices.

Conclusion

The concepts of compassion, kindness and humanity in dementia care are discussed within the paper. The ability to deliver care that is compassionate, kind and humanistic exists along a continuum across care settings – examples of excellent care sit alongside examples of very poor care and the reasons for this are explored together with discussion as to how health and social care staff can be trained and supported to deliver compassionate care.     

Alcohol consumption and dementia risk: a dose–response meta-analysis of prospective studies

It is widely believed that light-to-moderate alcohol intake may protect against dementia while excessive drinking may instead increase the risk. Nonetheless, these findings need cautious interpretations due to varying methodologies and lack of standard definition, which hindered our transferring into preventative practice. The objective of this study is to investigate the potential dose–response association between alcohol consumption and risk of dementia. A systematic search was conducted in electronic databases to identify relevant studies. Risk estimates were combined using a random-effect model. Eleven studies with 73,330 participants and 4586 cases for all-cause dementia (ACD), five studies with 52,715 participants and 1267 cases for Alzheimer’s dementia (AD) and four studies with 49,535 participants and 542 cases for vascular dementia were included. We observed a nonlinear association between alcohol consumption and ACD risk (p _nonlinearity < 0.05). The alcohol dose associated with lower risk of dementia was confined to at most 12.5 g/day, with the risk hitting bottom (RR ≈ 0.9) at roughly 6 g/day. Of note, the ACD risk seemed to be elevated (≈10%) when the dose surpasses certain levels: 23 drinks/week or 38 g/day. For the alcohol type, recommendation for wine is prioritized. The subgroup analysis further indicated that the effect of alcohol may be greater in younger adults (<60 years old) with regard to fighting against dementia. Modest alcohol consumption (≤12.5 g/day) is associated with a reduced risk of dementia with 6 g/day of alcohol conferring a lower risk than other levels while excessive drinking (≥38 g/day) may instead elevate the risk.     

The Mental Capacity Act 2005: promoting the citizenship of people with dementia?

The Mental Capacity Act 2005 came into force in England and Wales during 2007. The Act enshrines a legal right to autonomy (negative and positive) of people lacking decision-making capacity, such as people with dementia. This paper examines the extent to which the legislation promotes the social citizenship of people with dementia, focusing on its effectiveness in protecting liberty and promoting self-determination and in providing social rights to facilitate autonomy. In particular, the author considers the degree to which the Act will facilitate decision-making by people with dementia, centring on decisions relating to where to live (at home or in an institution). In addition, the historical detention (usually informal) of people with dementia in institutional care, and the role of the Act in promoting recognition of their right to liberty, is highlighted. However, the author points out that the civil rights to liberty and self-determination accorded under the Act--particularly the right to decide where to live--are restricted rights only, as the views of the person lacking capacity can be over-ridden by the decisions of others. In addition, the facilitation of these civil rights is constrained by a lack of access to social rights, particularly the availability of domiciliary and community services to avoid institutional admission. Consequently, whilst the legislation promotes the social citizenship of people with dementia, it has limited capacity to facilitate their full citizenship status.     

Vitamin D status and risk of dementia and Alzheimer’s disease: A meta-analysis of dose-response†

Objective: We aimed to test the dose-response association of serum 25(OH)D and risk of dementia and Alzheimer’s disease (AD).

Methods: We performed a systematic search of PubMed and Scopus from database inception up to September 2017. Longitudinal cohort studies reporting risk estimates of incident dementia or AD in the general population, and for three or more quantitative categories of serum 25(OH)D were included. Pooled hazard ratios (HRs) were calculated using fixed-effects/random-effects models.

Results: Seven prospective cohort studies and one retrospective cohort study (total n?=?28,354) involving 1953 cases of dementia and 1607 cases of AD were included. The pooled HRs of dementia and AD were 1.09 (95%CI: 0.95, 1.24) and 1.19 (95%CI: 0.96, 1.41) for vitamin D insufficiency (10–20?ng/ml), and 1.33 (95%CI: 1.08, 1.58) and 1.31 (95%CI: 0.98, 1.65) for deficiency (<10?ng/ml), respectively. The lower risk of dementia was observed at serum 25(OH)D of ～25?ng/ml, whereas the risk of AD decreased continuously along with the increase of serum 25(OH)D up to ～35?ng/ml.

Conclusion: Higher levels of serum 25(OH)D was associated with a lower risk of dementia and AD, but we have no conclusive evidence regarding serum 25(OH)D levels of >35?ng/ml.     

Longitudinal and postural changes of blood pressure predict dementia: the Malmö Preventive Project

The role of blood pressure (BP) changes in dementia is debatable. We aimed to analyse how resting and postural BP changes relate to incident dementia over a long-term follow-up. In the prospective population-based Malmö Preventive Project, 18,240 study participants (mean age: 45 ± 7 years, 63% male) were examined between 1974 and 1992 with resting and standing BP measurement, and re-examined between 2002 and 2006 at mean age of 68 ± 6 years with resting BP. A total of 428 participants (2.3%) were diagnosed with dementia through Dec 31, 2009. The association of resting and postural BP changes with risk of dementia was studied using multivariable-adjusted Cox regression models controlling for traditional risk factors. Diastolic BP (DBP) decrease on standing indicated higher risk of dementia [Hazard ratio (HR) per 10 mmHg: 1.22; 95% confidence interval (CI) 1.01–1.44, p = 0.036], which was mainly driven by increased risk in normotensive individuals. Higher systolic (SBP) and diastolic BP at re-examination was associated with lower risk of dementia (HR per 10 mmHg: 0.94; 95% CI 0.89–0.99, p = 0.011; and 0.87; 0.78–0.96, p = 0.006, respectively). Extreme decrease in SBP/DBP between baseline and re-examination (4th quartile; ?7 ± 12/?15 ± 7 mmHg, respectively) indicated higher risk of dementia (HR 1.46; 95% CI 1.11–1.93, p = 0.008, and 1.54; 95% CI 1.14–2.08, p = 0.005; respectively) compared with reference group characterised by pronounced BP increase over the same period (1st quartile; +44 ± 13/+15 ± 7 mmHg). Diastolic BP decrease on standing in the middle age, decline in BP between middle-and advanced age, and lower BP in advanced age are independent risk factors of developing dementia.     

Association of cortical β-amyloid with erythrocyte membrane monounsaturated and saturated fatty acids in older adults at risk of dementia

Objectives

We examined the relationships between erythrocyte membrane monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs) and cortical β-amyloid (Aβ) load in older adults reporting subjective memory complaints.

Design

This is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial.

Setting

French community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia.

Participants

Participants of this study were 61 individuals from the placebo arm of the MAPT trial with data on erythrocyte membrane fatty acid levels and cortical Aβ load.

Measurements

Cortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Fatty acids were measured in erythrocyte cell membranes using gas chromatography. Associations between erythrocyte membrane MUFAs and SFAs and cortical Aβ load were explored using adjusted multiple linear regression models and were considered significant at p ≤ 0.005 (10 comparisons) after correction for multiple testing.

Results

We found no significant associations between fatty acids and cortical Aβ load using multiple linear regression adjusted for age, sex, education, cognition, PET-scan to clinical assessment interval, PET-scan to blood collection interval and apolipoprotein E (ApoE) status. The association closest to significance was that between erythrocyte membrane stearic acid and Aβ (B-coefficient 0.03, 95 % CI: 0.00,0.05, p = 0.05). This association, although statistically non-significant, appeared to be stronger amongst ApoE ε4 carriers (B-coefficient 0.04, 95 % CI: -0.01,0.09, p = 0.08) compared to ApoE ε4 non-carriers (B-coefficient 0.02, 95 % CI: -0.01,0.05, p = 0.18) in age and sex stratified analysis.

Conclusion

Future research in the form of large longitudinal observational study is needed to validate our findings, particularly regarding the potential association of stearic acid with cortical Aβ.

     

Analysing time to event data in dementia prevention trials: The example of the guidage study of EGB761®

Time-to-event analysis is frequently used in medical research to investigate potential diseasemodifying treatments in neurodegenerative diseases. Potential treatment effects are generally evaluated using the logrank test, which has optimal power and sensitivity when the treatment effect (hazard ratio) is constant over time. However, there is generally no prior information as to how the hazard ratio for the event of interest actually evolves. In these cases, the logrank test is not necessarily the most appropriate to use. When the hazard ratio is expected to decrease or increase over time, alternative statistical tests such as the Fleming-Harrington test, provide a better sensitivity. An example of this comes from a large, five-year randomised, placebo-controlled prevention trial (GuidAge) in 2854 community-based subjects making spontaneous memory complaints to their family physicians, which evaluated whether treatment with EGb761® can modify the risk of developing AD. The primary outcome measure was the time to conversion from memory complaint to Alzheimer’s type dementia. Although there was no significant difference in the hazard function of conversion between the two treatment groups according to the preplanned logrank test, a significant treatment-by-time interaction for the incidence of AD was observed in a protocol-specified subgroup analysis, suggesting that the hazard ratio is not constant over time. For this reason, additional post hoc analyses were performed using the Fleming-Harrington test to evaluate whether there was a signal of a late effect of EGb761®. Applying the Fleming-Harrington test, the hazard function for conversion to dementia in the placebo group was significantly different from that in the EGb761® treatment group (p = 0.0054), suggesting a late effect of EGb761®. Since this was a post hoc analysis, no definitive conclusions can be drawn as to the effectiveness of the treatment. This post hoc analysis illustrates the interest of performing another randomised clinical trial of EGb761® explicitly testing the hypothesis of a late treatment effect, as well as of using of better adapted statistical approaches for long term preventive trials when it is expected that prevention cannot have an immediate effect but rather a delayed effect that increases over time.