Background:

Studies that have investigated the relation between depression and the type, nature, extent and outcome of general hospital admissions have been limited by their retrospective designs and focus on specific clinical populations. We explored this relation prospectively in a large, community-based sample of older men.

Methods:

A cohort of 5411 men aged 69 years and older enrolled in the Health in Men Study was assessed at baseline for depressive symptoms, defined as a score of 7 or higher on the 15-item Geriatric Depression Scale. Participants were followed for 2 years for occurrence and number of hospital admissions, type of hospital admission, length of hospital stay and inpatient death as recorded in the Western Australian Data Linkage System.

Results:

Of 339 men with depressive symptoms, 152 (44.8%) had at least 1 emergency hospital admission, compared with 1164 of 5072 (22.9%) nondepressed men (p < 0.001). In multivariate analyses, the presence of depressive symptoms was a significant independent predictor of hospital admission (hazard ratio 1.67, 95% confidence interval [CI] 1.38–2.01), number of hospital admissions (incidence rate ratio [IRR] 1.22, 95% CI 1.07–1.39) and total length of hospital stay (IRR 1.65, 95% CI 1.36–2.01).

Interpretation:

Participants with depressive symptoms were at higher risk of hospital admission for nonpsychiatric conditions and were more likely to have longer hospital stays and worse hospital outcomes, compared with nondepressed participants. These results highlight the potential to target this high-risk group to reduce the burden of health care costs in an aging population.

Objective

To describe how criteria for amnestic Mild Cognitive Impairment (aMCI) have been operationalised in randomised controlled clinical trials (RCTs).

Design

Systematic review.

Information sources

EMBASE, PubMed and PSYCHInfo were searched from their inception to February 2012. Electronic clinical trial registries were also searched (February 2012).

Study selection

RCTs were included where participant selection was made using Petersen et al-defined aMCI. There was no restriction on intervention type or the outcome tested.

Data extraction

For each trial, we extracted information on study design, demographics, exclusion criteria and the operationalisation strategy for the five aMCI diagnostic criteria including: (1) memory complaint, (2) normal general cognitive function, (3) memory impairment, (4) no functional impairment and (5) no dementia.

Results

223 articles and 278 registered trials were reviewed, of which 22 met inclusion criteria. Various methods were applied for operationalising aMCI criteria resulting in variability in participant selection. Memory complaint and assessment of general cognitive function were the most consistently measured criteria. There was large heterogeneity in the neuropsychological methods used to determine memory impairment. It was not possible to assess the impact of these differences on case selection accuracy for dementia prediction. Further limitations include selective and unclear reporting of how each of the criteria was measured.

Conclusions

The results highlight the urgent need for a standardised approach to map aMCI. Lack of uniformity in clinical diagnosis, however, is not exclusively a problem for MCI but also for other clinical states such as dementia including Alzheimer's disease, Lewy Body, frontotemporal or vascular dementia. Defining a uniform approach to MCI classification, or indeed for any classification concept within the field of dementia, should be a priority if further trials are to be undertaken in the older aged population based on these concepts.

Background

Population ageing over the first half of this century is likely to lead to dramatic increases in the prevalence of dementia. This will affect all regions of the world, but particularly developing regions. Dementia projections have been used extensively to support policy. It is therefore important these projections are as accurate as possible.

Discussion

In this paper we provide a commentary on studies projecting the future prevalence of dementia for the world or for individual continents. We identify some important limitations of the methods used in published projections and provide recommendations to improve the accuracy of future projections, and allow for the checking of the accuracy of the predictions.

Summary

Accurate projections of dementia incidence, at both the global and local level, are essential for healthcare planners.

Background

Three factors commonly used as measures of cognitive lifestyle are education, occupation, and social engagement. This study determined the relative importance of each variable to long term cognitive health in those with and without severe cognitive impairment.

Methods

Data came from 12,470 participants from a multi-centre population-based cohort (Medical Research Council Cognitive Function and Ageing Study). Respondents were aged 65 years and over and were followed-up over 16 years. Cognitive states of no impairment, slight impairment, and moderate/severe impairment were defined, based on scores from the Mini-Mental State Examination. Multi-state modelling was used to investigate links between component cognitive lifestyle variables, cognitive state transitions over time, and death.

Results

Higher educational attainment and a more complex mid-life occupation were associated with a lower risk of moving from a non-impaired to a slightly impaired state (hazard ratios 0.5 and 0.8), but with increased mortality from a severely impaired state (1.3 and 1.1). More socially engaged individuals had a decreased risk of moving from a slightly impaired state to a moderately/severely impaired state (0.7). All three cognitive lifestyle variables were linked to an increased chance of cognitive recovery back to the non-impaired state.

Conclusions

In those without severe cognitive impairment, different aspects of cognitive lifestyle predict positive cognitive transitions over time, and in those with severe cognitive impairment, a reduced life-expectancy. An active cognitive lifestyle is therefore linked to compression of cognitive morbidity in late life.

Psychotic symptoms occur in approximately 40% of subjects with Alzheimer’s disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWAS) to identify loci that a) increase susceptibility to an AD and subsequent psychotic symptoms; or b) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD−P) and 5659 controls were drawn from GERAD1, the NIA-LOAD family study and the University of Pittsburgh ADRC GWAS. Unobserved genotypes were imputed to provide data on > 1.8 million SNPs. Analyses in each dataset were completed comparing a) AD+P to AD−P cases, and b) AD+P cases with controls (GERAD1, ADRC only). Aside from the APOE locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; ‘AD+PvAD−P’ P=2.85 × 10−7; ‘AD+PvControls’ P=1.11 × 10−4). SNPs upstream of SLC2A9 (rs6834555, P=3.0×10−7) and within VSNL1 (rs4038131, P=5.9×10−7) showed strongest evidence for association with AD+P when compared to controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterised.

A systematic review of qualitative studies conducted by Frances Bunn and colleagues identifies and describes the experiences of patients and caregivers on receiving and adapting to a diagnosis of dementia.

Background

Early diagnosis and intervention for people with dementia is increasingly considered a priority, but practitioners are concerned with the effects of earlier diagnosis and interventions on patients and caregivers. This systematic review evaluates the qualitative evidence about how people accommodate and adapt to the diagnosis of dementia and its immediate consequences, to guide practice.

Methods and Findings

We systematically reviewed qualitative studies exploring experiences of community-dwelling individuals with dementia, and their carers, around diagnosis and the transition to becoming a person with dementia. We searched PubMed, PsychINFO, Embase, CINAHL, and the British Nursing Index (all searched in May 2010 with no date restrictions; PubMed search updated in February 2012), checked reference lists, and undertook citation searches in PubMed and Google Scholar (ongoing to September 2011). We used thematic synthesis to identify key themes, commonalities, barriers to earlier diagnosis, and support identified as helpful. We identified 126 papers reporting 102 studies including a total of 3,095 participants. Three overarching themes emerged from our analysis: (1) pathways through diagnosis, including its impact on identity, roles, and relationships; (2) resolving conflicts to accommodate a diagnosis, including the acceptability of support, focusing on the present or the future, and the use or avoidance of knowledge; and (3) strategies and support to minimise the impact of dementia. Consistent barriers to diagnosis include stigma, normalisation of symptoms, and lack of knowledge. Studies report a lack of specialist support particularly post-diagnosis.

Conclusions

There is an extensive body of qualitative literature on the experiences of community-dwelling individuals with dementia on receiving and adapting to a diagnosis of dementia. We present a thematic analysis that could be useful to professionals working with people with dementia. We suggest that research emphasis should shift towards the development and evaluation of interventions, particularly those providing support after diagnosis.

Please see later in the article for the Editors' Summary.

Editors' Summary

Background

Dementia is a decline in mental ability severe enough to interfere with daily life. Alzheimer disease is the most common type of dementia. People with dementia usually have problems with two or more cognitive functions—thinking, language, memory, understanding, and judgment. Dementia is rare before the age of 65, but about a quarter of people over 85 have dementia. Because more people live longer these days, the number of patients with dementia is increasing. It is estimated that today between 40 and 50 million people live with dementia worldwide. By 2050, this number is expected to triple.

One way to study what dementia means to patients and their carers (most often spouses or other family members) is through qualitative research. Qualitative research aims to develop an in-depth understanding of individuals' experiences and behavior, as well as the reasons for their feelings and actions. In qualitative studies, researchers interview patients, their families, and doctors. When the studies are published, they usually contain direct quotations from interviews as well as summaries by the scientists who designed the interviews and analyzed the responses.

Why Was This Study Done?

This study was done to better understand the experiences and attitudes of patients and their carers surrounding dementia diagnosis. It focused on patients who lived and were cared for within the community (as opposed to people living in senior care facilities or other institutions). Most cases of dementia are progressive, meaning symptoms get worse over time. Diagnosis often happens at an advanced stage of the disease, and some patients never receive a formal diagnosis. This could have many possible reasons, including unawareness or denial of symptoms by patients and people close to them. The study was also trying to understand barriers to early diagnosis and what type of support is useful for newly diagnosed patients and carers.

What Did the Researchers Do and Find?

The researchers conducted a systematic search for published qualitative research studies that reported on the experience, beliefs, feelings, and attitudes surrounding dementia diagnosis. They identified and reviewed 102 such studies. Among the quotations and summaries of the individual studies, they looked for prominent and recurring themes. They also compared and contrasted the respective experiences of patients and carers.

Overall, they found that the complexity and variety of responses to a diagnosis of dementia means that making the diagnosis and conveying it to patients and carers is challenging. Negative connotations associated with dementia, inconsistent symptoms, and not knowing enough about the signs and symptoms were commonly reported barriers to early dementia diagnosis. It was often the carer who initiated the search for help from a doctor, and among patients, willingness and readiness to receive a diagnosis varied. Being told one had dementia had a big impact on a patient's identity and often caused feelings of loss, anger, fear, and frustration. Spouses had to adjust to increasingly unequal relationships and the transition to a role as carer. The strain associated with this often caused health problems in the carers as well. On the other hand, studies examining the experience of couples often reported that they found ways to continue working together as a team.

Adjusting to a dementia diagnosis is a complex process. Initially, most patients and carers experienced conflicts, for example, between autonomy and safety, between recognizing the need for help but reluctance to accept it, or between living in the present and dealing with anxiety about and preparing for the future. As these were resolved and as the disease progressed, the attitudes of patients and carers towards dementia often became more balanced and accepting. Many patients and their families adopted strategies to cope with the impact of dementia on their lives in order to manage the disease and maintain some sort of normal life. These included practical strategies involving reminders, social strategies such as relying on family support, and emotional strategies such as using humor. At some point many patients and carers reported that they were able to adopt positive mindsets and incorporate dementia in their lives.

The studies also pointed to an urgent need for support from outside the family, both right after diagnosis and subsequently. General practitioners and family physicians have important roles in helping patients and carers to get access to information, social and psychological support, and community care. The need for information was reported to be ongoing and varied, and meeting it required a variety of sources and formats. Key needs for patients and carers mentioned in the studies include information on financial aids and entitlements early on, and continued access to supportive professionals and specialists.

What Do These Findings Mean?

Qualitative studies to date on how patients and carers respond to a diagnosis of dementia provide a fairly detailed picture of their experiences. The summary provided here should help professionals to understand better the challenges patients and carers face around the time of diagnosis as well as their immediate and evolving needs. The results also suggest that future research should focus on the development and evaluation of ways to meet those needs.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001331.

Wikipedia has pages on dementia and qualitative research (note that Wikipedia is a free online encyclopedia that anyone can edit)

Alzheimer Europe, an umbrella organization of 34 Alzheimer associations from 30 countries across Europe, has a page on the different approaches to research

The UK Department of Health has pages on dementia, including guidelines for carers of people with dementia

MedlinePlus also has information about dementia

Alzheimer's disease (AD) is a progressive neurodegenerative disease and in its familial form is associated with mutations in the amyloid precursor protein (APP) and the presenilins (PSs). Much data regarding the interactions of APP, its proteolytic fragments and PS have been generated, expanding our understanding of the roles of these proteins in mechanisms underlying cognitive function and revealing many complex relationships with wide ranging cellular systems. In this review, we examine the multiple interactions of APP and its proteolytic fragments with other neuronal systems in terms of feedback loops and use these relationships to build a map. We highlight the complexity involved in the APP proteolytic system and discuss alternative perspectives on the roles of APP and its proteolytic fragments in dynamic processes associated with disease progression in AD. We highlight areas where data are missing and suggest potential confounding factors. We suggest that a systems biology approach enhances representations of the data and may be more useful in modelling both normal cognition and disease processes.

Objective:

Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain.

Methods:

We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis.

Results:

In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD.

Conclusion:

The current evidence linking common mtDNA variations with AD is not compelling.

Background

Whilst many studies have analysed predictors of longitudinal cognitive decline, few have described their impact on population distributions of cognition by age cohort. The aim of this paper was to examine whether gender, education, social class and birth cohort affect how mean population cognition changes with age.

Methods

The Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) is a multi-centre population based longitudinal study of 13,004 individuals in England and Wales. Using ten years of follow-up data, mean Mini-mental State Examination (MMSE) scores were modelled by age and birth cohort adjusting for non-random drop-out. The model included terms to estimate cohort effects. Results are presented for five year age bands between 65–95 years.

Results

At a population level, women show greater change in MMSE scores with age than men. Populations with lower education level and manual work also show similar effects. More recent birth cohorts have slightly higher scores.

Conclusion

Longitudinal data can allow examination of population patterns by gender, educational level, social class and cohort. Each of these major socio-demographic factors shows some effect on whole population change in MMSE with age.

Recent studies suggest that delirium is associated with risk of dementia and also acceleration of decline in existing dementia. However, previous studies may have been confounded by incomplete ascertainment of cognitive status at baseline. Herein, we used a true population sample to determine if delirium is a risk factor for incident dementia and cognitive decline. We also examined the effect of delirium at the pathological level by determining associations between dementia and neuropathological markers of dementia in patients with and without a history of delirium. The Vantaa 85+ study examined 553 individuals (92% of those eligible) aged ≥85 years at baseline, 3, 5, 8 and 10 years. Brain autopsy was performed in 52%. Fixed and random-effects regression models were used to assess associations between (i) delirium and incident dementia and (ii) decline in Mini-Mental State Examination scores in the whole group. The relationship between dementia and common neuropathological markers (Alzheimer-type, infarcts and Lewy-body) was modelled, stratified by history of delirium. Delirium increased the risk of incident dementia (odds ratio 8.7, 95% confidence interval 2.1–35). Delirium was also associated with worsening dementia severity (odds ratio 3.1, 95% confidence interval 1.5–6.3) as well as deterioration in global function score (odds ratio 2.8, 95% confidence interval 1.4–5.5). In the whole study population, delirium was associated with loss of 1.0 more Mini-Mental State Examination points per year (95% confidence interval 0.11–1.89) than those with no history of delirium. In individuals with dementia and no history of delirium (n = 232), all pathologies were significantly associated with dementia. However, in individuals with delirium and dementia (n = 58), no relationship between dementia and these markers was found. For example, higher Braak stage was associated with dementia when no history of delirium (odds ratio 2.0, 95% confidence interval 1.1–3.5, P = 0.02), but in those with a history of delirium, there was no significant relationship (odds ratio 1.2, 95% confidence interval 0.2–6.7, P = 0.85). This trend for odds ratios to be closer to unity in the delirium and dementia group was observed for neuritic amyloid, apolipoprotein ε status, presence of infarcts, α-synucleinopathy and neuronal loss in substantia nigra. These findings are the first to demonstrate in a true population study that delirium is a strong risk factor for incident dementia and cognitive decline in the oldest-old. However, in this study, the relationship did not appear to be mediated by classical neuropathologies associated with dementia.

Kenneth Coburn and colleagues report findings from a randomized trial evaluating the effects of a complex nursing intervention on mortality risk among older individuals diagnosed with chronic health conditions.

Background

Improving the health of chronically ill older adults is a major challenge facing modern health care systems. A community-based nursing intervention developed by Health Quality Partners (HQP) was one of 15 different models of care coordination tested in randomized controlled trials within the Medicare Coordinated Care Demonstration (MCCD), a national US study. Evaluation of the HQP program began in 2002. The study reported here was designed to evaluate the survival impact of the HQP program versus usual care up to five years post-enrollment.

Methods and Findings

HQP enrolled 1,736 adults aged 65 and over, with one or more eligible chronic conditions (coronary artery disease, heart failure, diabetes, asthma, hypertension, or hyperlipidemia) during the first six years of the study. The intervention group (n = 873) was offered a comprehensive, integrated, and tightly managed system of care coordination, disease management, and preventive services provided by community-based nurse care managers working collaboratively with primary care providers. The control group (n = 863) received usual care. Overall, a 25% lower relative risk of death (hazard ratio [HR] 0.75 [95% CI 0.57–1.00], p = 0.047) was observed among intervention participants with 86 (9.9%) deaths in the intervention group and 111 (12.9%) deaths in the control group during a mean follow-up of 4.2 years. When covariates for sex, age group, primary diagnosis, perceived health, number of medications taken, hospital stays in the past 6 months, and tobacco use were included, the adjusted HR was 0.73 (95% CI 0.55–0.98, p = 0.033). Subgroup analyses did not demonstrate statistically significant interaction effects for any subgroup. No suspected program-related adverse events were identified.

Conclusions

The HQP model of community-based nurse care management appeared to reduce all-cause mortality in chronically ill older adults. Limitations of the study are that few low-income and non-white individuals were enrolled and implementation was in a single geographic region of the US. Additional research to confirm these findings and determine the model's scalability and generalizability is warranted.

Trial Registration

ClinicalTrials.gov NCT01071967

Please see later in the article for the Editors' Summary

Editors' Summary

Background

In almost every country in the world, the proportion of people aged over 60 years is growing faster than any other age group because of increased life expectancy. This demographic change has several implications for public health, especially as older age is a risk factor for many chronic diseases—diseases of long duration and generally slow progression. Chronic diseases, such as heart disease, stroke, cancer, chronic respiratory diseases, and diabetes, are by far the leading cause of death in the world, representing almost two-thirds of all deaths. Therefore in most countries, the challenge of managing increasingly ageing populations who have chronic illnesses demands an urgent response and countries such as the United States are actively researching possible solutions.

Why Was This Study Done?

Some studies suggest that innovations in chronic disease management that are led by nurses may help address the epidemic of chronic diseases by increasing the quality and reducing the cost of care. However, to date, reports of the evaluation of such interventions lack rigor and do not provide evidence of improved long-term health outcomes or reduced health care costs. So in this study, the researchers used the gold standard of research, a randomized controlled trial, to examine the impact of a community-based nurse care management model for older adults with chronic illnesses in the United States as part of a series of studies supported by the Centers for Medicare and Medicaid Services.

What Did the Researchers Do and Find?

The researchers recruited eligible patients aged 65 years and over with heart failure, coronary heart disease, asthma, diabetes, hypertension, and/or hyperlipidemia who received traditional Medicare—a fee for service insurance scheme in which beneficiaries can choose to receive their care from any Medicare provider—from participating primary care practices in Pennsylvania. The researchers then categorized patients according to their risk on the basis of several factors including the number of chronic diseases each individual had before randomizing patients to receive usual care or the nurse-led intervention. The intervention included an individualized plan comprising education, symptom monitoring, medication, counseling for adherence, help identifying, arranging, and monitoring community health and social service referrals in addition to group interventions such as weight loss maintenance and exercise classes. The researchers checked whether any participating patients had died by using the online Social Security Death Master File. Then the researchers used a statistical model to calculate the risk of death in both groups.

Of the 1,736 patients the researchers recruited into the trial, 873 were randomized to receive the intervention and 863 were in the control group (usual care). The researchers found that 86 (9.9%) participants in the intervention group and 111 (12.9%) participants in the control group died during the study period, representing a 25% lower relative risk of death among the intervention group. However, when the researchers considered other factors, such as sex, age group, primary diagnosis, perceived health, number of medications taken, hospital stays in the past 6 months, and tobacco use in their statistical model, this risk was slightly altered—0.73 risk of death in the intervention group.

What Do These Findings Mean?

These findings suggest that that community-based nurse care management is associated with a reduction in all-cause mortality among older adults with chronic illnesses who are beneficiaries of the fee for service Medicare scheme in the United States. These findings also support the important role of nurses in improving health outcomes in this group of patients and show the feasibility of implementing this program in collaboration with primary care practices. Future research is needed to test the adaptability, scalability, and generalizability of this model of care.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001265.

This study is further discussed in a PLoS Medicine Perspective by Arlene Bierman

Information about the Centers for Medicare and Medicaid Services is available

The World Health Organization provides statistics on the prevalence of both chronic illness and ageing

Heath Quality Partners provide information about the study

Introduction

Behavioural and psychological symptoms of dementia (BPS) include depressive symptoms, anxiety, apathy, sleep problems, irritability, psychosis, wandering, elation and agitation, and are common in the non-demented and demented population.

Methods

We have undertaken a systematic review of reviews to give a broad overview of the prevalence, course, biological and psychosocial associations, care and outcomes of BPS in the older or demented population, and highlight limitations and gaps in existing research. Embase and Medline were searched for systematic reviews using search terms for BPS, dementia and ageing.

Results

Thirty-six reviews were identified. Most investigated the prevalence or course of symptoms, while few reviewed the effects of BPS on outcomes and care. BPS were found to occur in non-demented, cognitively impaired and demented people, but reported estimates vary widely. Biological factors associated with BPS in dementia include genetic factors, homocysteine levels and vascular changes. Psychosocial factors increase risk of BPS; however, across studies and between symptoms findings are inconsistent. BPS have been associated with burden of care, caregiver's general health and caregiver depression scores, but findings are limited regarding institutionalisation, quality of life and disease outcome.

Conclusions

Limitations of reviews include a lack of high quality reviews, particularly of BPS other than depression. Limitations of original studies include heterogeneity in study design particularly related to measurement of BPS, level of cognitive impairment, population characteristics and participant recruitment. It is our recommendation that more high quality reviews, including all BPS, and longitudinal studies with larger sample sizes that use frequently cited instruments to measure BPS are undertaken. A better understanding of the risk factors and course of BPS will inform prevention, treatment and management and possibly improve quality of life for the patients and their carers.

Background: physical functioning describes the underlying abilities that make activities necessary for independent living in the community possible.

Objective: to test self-reported and objective measures of physical functioning in predicting subsequent disability in cooking, shopping and housework.

Design: we used data from the first and second waves of the Survey of Health, Ageing and Retirement in Europe. The respondents were asked about physical functioning (climbing, pulling/pushing, stooping/crouching/kneeling, lifting/carrying and reaching/extending were comparable) and they had their grip strength and walking speed measured.

Participants: men and women aged 65 years or over who reported no disability in cooking, shopping and housework at baseline were included in the analysis. There were 6,841 individuals for whom data on disability status at follow-up were available.

Methods: Poisson regression was used to calculate relative risks for the associations between self-reported and objective measures of physical functioning with disability at 2 years, adjusting for age, gender, educational level, cognitive function and chronic conditions.

Results: those with limitations in physical functioning at baseline more frequently reported subsequent disability. Walking ability was most strongly associated with disability; climbing, pulling/pushing, lifting/carrying and reaching/extending were comparable (picking was non-significant). Similar results were obtained with grip strength and walking speed.

Conclusions: both self-reports and objective measures capture information on the functional ability of older people that can be used to predict disability onset. Objective measures offer little to the development of intervention strategies, whereas self-reports provide some insight into the demands of the environment, being more amenable to interventions.

The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques—which are frequently surrounded by dystrophic neurites—and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis.

Background

It is known that people who suffer from depression are more likely to have other physical illnesses, but the extent of the association between depression and non-psychiatric hospitalisation episodes has never been researched in great depth. We therefore aimed to investigate whether depressed middle-aged and older people were more likely to be hospitalised for causes other than mental illnesses, and whether the outcomes for this group of people were less favourable.

Methods & Findings

Hospital events from 1995 to 2006 were obtained from the Dutch National Medical Register and linked to participants of the Longitudinal Aging Study Amsterdam (LASA). Linkage was accomplished in 97% of the LASA sample by matching gender, year of birth and postal code. Depression was measured at each wave point of the LASA study using the Centre for Epidemiologic Studies Depression (CES-D). Hospital outcomes including admission, length of stay, readmission and death while in hospital were recorded at 6, 12 and 24 months intervals after each LASA interview. Generalised Estimating Equation models were also used to investigate potential confounders. After 12 months, 14% of depressed people were hospitalised compared to 10% of non-depressed individuals. There was a 2-fold increase in deaths while in hospital amongst the depressed (0.8% vs 0.4%), who also had longer total length of stay (2.6 days vs 1.4 days). Chronic illnesses and functional limitations had major attenuating effects, but depression was found to be an independent risk factor for length of stay after full adjustment (OR = 1.33, 95% CI: 1.22–1.46 after 12 months).

Conclusions

Depression in middle and old age is associated with non-psychiatric hospitalisation, longer length of stay and higher mortality in clinical settings. Targeting of this high-risk group could reduce the financial, medical and social burden related to hospital admission.

Background

Anxiety is a common mental disorder among older people who live in the Western world, yet little is known about its prevalence in low- and middle-income countries.

Aims

We investigated the prevalence of anxiety and its correlates among older adults in low- and middle-income countries with diverse cultures.

Method

Cross-sectional surveys of all residents aged 65 or over (n = 15 021) in 11 catchment sites in 7 countries (China, India, Cuba, Dominican Republic, Venezuela, Mexico and Peru) were carried out as part of the 10/66 collaboration. Anxiety was measured by using the Geriatric Mental State Examination (GMS) and the Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT) diagnostic algorithm.

Results

The age- and gender-standardised prevalence of anxiety varied greatly across sites, ranging from 0.1% (95% CI 0.0–0.3) in rural China to 9.6% (95% CI 6.2–13.1) in urban Peru. Urban centres had higher estimates of anxiety than their rural counterparts with adjusted (age, gender and site) odds ratios of 2.9 (95% CI 1.7–5.3). Age, gender, socioeconomic status and comorbid physical illnesses were all associated with a GMS/AGECAT diagnosis of anxiety, and so was disability (World Health Organization Disability Assessment Schedule II).

Conclusions

Anxiety is common in Latin America. Estimates from this region are similar to the ones from high-income European countries found in the literature. As demographic change will occur more rapidly in these countries, further research exploring the mental health of older people in developing areas is vital, with the inclusion of other specific anxiety disorders, along with evidence for strategies for supporting those with these disorders.

We sought to identify new susceptibility loci for Alzheimer’s disease (AD) through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer’s Disease Genetic Consortium (ADGC). First, we undertook a combined analysis of four genome-wide association datasets (Stage 1) and identified 10 novel variants with P≤1×10−5. These were tested for association in an independent sample (Stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (Stage 3). Meta-analyses of all data provide compelling evidence that ABCA7 (meta-P 4.5×10−17; including ADGC meta-P=5.0×10−21) and the MS4A gene cluster (rs610932, meta-P=1.8×10−14; including ADGC meta-P=1.2×10−16; rs670139, meta-P=1.4×10−9; including ADGC meta-P=1.1×10−10) are novel susceptibility loci for AD. Second, we observed independent evidence for association for three suggestive loci reported by the ADGC GWAS, which when combined shows genome-wide significance: CD2AP (GERAD+ P=8.0×10−4; including ADGC meta-P=8.6×10−9), CD33 (GERAD+ P=2.2×10−4; including ADGC meta-P=1.6×10−9) and EPHA1 (GERAD+ P=3.4×10−4; including ADGC meta-P=6.0×10−10). These findings support five novel susceptibility genes for AD.

Kimmo Herttua and colleagues showed that living alone is associated with a substantially increased risk of alcohol-related mortality, irrespective of gender, socioeconomic status, or cause of death, and that this effect was exacerbated after a price reduction in alcohol in 2004.

Background

Social isolation and living alone are increasingly common in industrialised countries. However, few studies have investigated the potential public health implications of this trend. We estimated the relative risk of death from alcohol-related causes among individuals living alone and determined whether this risk changed after a large reduction in alcohol prices.

Methods and Findings

We conducted a population-based natural experimental study of a change in the price of alcohol that occurred because of new laws enacted in Finland in January and March of 2004, utilising national registers. The data are based on an 11% sample of the Finnish population aged 15–79 y supplemented with an oversample of deaths. The oversample covered 80% of all deaths during the periods January 1, 2000–December 31, 2003 (the four years immediately before the price reduction of alcohol), and January 1, 2004–December 31, 2007 (the four years immediately after the price reduction). Alcohol-related mortality was defined using both underlying and contributory causes of death. During the 8-y follow-up about 18,200 persons died due to alcohol-related causes. Among married or cohabiting people the increase in alcohol-related mortality was small or non-existing between the periods 2000–2003 and 2004–2007, whereas for those living alone, this increase was substantial, especially in men and women aged 50–69 y. For liver disease in men, the most common fatal alcohol-related disease, the age-adjusted risk ratio associated with living alone was 3.7 (95% confidence interval 3.3, 4.1) before and 4.9 (95% CI 4.4, 5.4) after the price reduction (p<0.001 for difference in risk ratios). In women, the corresponding risk ratios were 1.7 (95% CI 1.4, 2.1) and 2.4 (95% CI 2.0, 2.9), respectively (p ≤ 0.01). Living alone was also associated with other mortality from alcohol-related diseases (range of risk ratios 2.3 to 8.0) as well as deaths from accidents and violence with alcohol as a contributing cause (risk ratios between 2.1 and 4.7), both before and after the price reduction.

Conclusions

Living alone is associated with a substantially increased risk of alcohol-related mortality, irrespective of gender, socioeconomic status, or the specific cause of death. The greater availability of alcohol in Finland after legislation-instituted price reductions in the first three months of 2004 increased in particular the relative excess in fatal liver disease among individuals living alone.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Throughout most of human history, people have lived in tight-knit communities where there was likely to be someone to turn to for help, advice, or company. But the modern way of life in industrialized countries is greatly reducing the quantity and quality of social relationships. Instead of living in extended families, many people now live miles away from their relatives, often living and working alone. Others commute long distances to work, which leaves little time for socializing with friends or relatives. And many delay or forgo getting married and having children. Consequently, loneliness and social isolation are getting more common. In the UK, according to a recent survey by the Mental Health Foundation, 10% of people often feel lonely, a third have a close friend or relative who they think is very lonely, and half think people are getting lonelier in general. Similarly, over the past two decades, there has been a three-fold increase in the number of Americans who say they have no close confidants.

Why Was This Study Done?

Some experts think that loneliness is bad for human health. They point to studies that show that people with fewer social relationships die earlier on average than people with more social relationships. But does loneliness increase the risk of dying from specific causes? It is important to investigate the relationship between loneliness and cause-specific mortality (death) because, if for example, loneliness increases the risk of dying from alcohol-related causes (heavy drinking causes liver and heart damage, increases the risk of some cancers, contributes to depression, and increases the risk of death by violence or accident), doctors could advise their patients who live alone about safe drinking. But, although loneliness is recognized as both a contributor to and a consequence of alcohol abuse, there have been no large, population-based studies on the association between living alone and alcohol-related mortality. In this population-based study, the researchers estimate the association between living alone (an indicator of a lack of social relationships) and death from alcohol-related causes in Finland for four years before and four years after an alcohol price reduction in 2004 that increased alcohol consumption.

What Did the Researchers Do and Find?

The researchers obtained information on about 80% of all people who died in Finland between 2000 and 2007 from Statistics Finland, which collects official Finnish statistics. During this period, about 18,200 people (two-thirds of whom lived alone) died from underlying alcohol-related causes (for example, liver disease and alcoholic poisoning) or contributory alcohol-related causes (for example, accidents, violence, and cardiovascular disease, with alcohol as a contributing cause). Among married and cohabiting people, the rate of alcohol-related mortality was similar in 2000–2003 and 2004–2007 but for people living alone (particularly those aged 50–69 years) the 2004 alcohol price reduction substantially increased the alcohol-related mortality rate. For liver disease in men, the risk ratio associated with living alone was 3.7 before and 4.9 after the price reduction. That is, between 2000 and 2003, men living alone were 3.7 times more likely to die of liver disease than married or cohabiting men; between 2004 and 2007, they were 4.9 times more likely to die of liver disease. In women, the corresponding risk ratios for liver disease were 1.7 and 2.4, respectively. Living alone was also associated with an increased risk of dying from other alcohol-related diseases and accidents and violence both before and after the price reduction.

What Do These Findings Mean?

These findings indicate that, in Finland, living alone is associated with an increased risk of alcohol-related mortality. Because of the study design, it is impossible to say whether living alone is a cause or a consequence of alcohol abuse, but the greater increase in alcohol-related deaths (particularly fatal liver disease) among people living alone compared to married and cohabiting people after the alcohol price reduction suggests that people living alone are more vulnerable to the adverse effects of increased alcohol availability. Further research in other countries is now needed to identify whether living alone is a cause or effect of alcohol abuse and to extend these findings to cultures where the pattern of alcohol consumption is different. However, the findings of this natural experiment suggest that living alone should be regarded as a potential risk marker for death from alcohol-related causes.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001094.

The Mental Health America Live Your Life Well webpage includes information about how social relationships improve mental and physical health

The Mental Health Foundation (a UK charity) presents the report The Lonely Society?

The US National Institute on Alcohol Abuse and Alcoholism has information about alcohol and its effects on health

The US Centers for Disease Control and Prevention has a website on alcohol and public health that includes information on the health risks of excessive drinking

The UK National Health Service Choices website provides detailed information about drinking and alcohol, including information on the risks of drinking too much, and personal stories about alcohol problems, including stories from people living alone (My drinks diary shock and I used to drink all day)

MedlinePlus provides links to many other resources on alcohol

Background

Previous investigations of test re-test reliability of the Mini-Mental State Examination (MMSE) have used correlations and statistics such as Cronbach's α to assess consistency. In practice, the MMSE is usually used to group individuals into cognitive states. The reliability of this grouping (state based approach) has not been fully explored.

Methods

MMSE data were collected on a subset of 2,275 older participants (≥ 65 years) from the population-based Medical Research Council Cognitive Function and Ageing Study. Two measurements taken approximately two months apart were used to investigate three state-based categorisations. Descriptive statistics were used to determine how many people remained in the same cognitive group or went up or down groups. Weighted logistic regression was used to identify predictive characteristics of those who moved group.

Results

The proportion of people who remained in the same MMSE group at screen and follow-up assessment ranged from 58% to 78%. The proportion of individuals who went up one or more groups was roughly equal to the proportion that went down one or more groups; most of the change occurred when measurements were close to the cut-points. There was no consistently significant predictor for changing cognitive group.

Conclusion

A state-based approach to analysing the reliability of the MMSE provided similar results to correlation analyses. State-based models of cognitive change or individual trajectory models using raw scores need multiple waves to help overcome natural variation in MMSE scores and to help identify true cognitive change.

A recent genome-wide association (GWA) study of late-onset Alzheimer's disease (LOAD) identified 15 novel single nucleotide polymorphisms (SNPs) independent of ApoE. We hypothesized that variants associated with LOAD are also associated with poor cognitive function in elderly populations. We measured additive associations between the five most strongly associated LOAD SNPs and grouped Mini Mental State Examination (MMSE) scores. Variants were genotyped in respondents (mean age 79yrs) from the Oxford Healthy Aging project (OHAP) and other sites of the MRC Cognitive Function and Aging Study (MRC-CFAS). In adjusted ordinal logistic models, two variants were associated with poorer cognitive function: rs11622883 (OR=1.14, 95%CI: 1.01 to 1.28, p=0.040) and rs505058 (OR=1.29, 95% CI: 1.02 to 1.64, p=0.036). These SNPs are close to a SERPINA gene cluster and within LMNA respectively. The mechanisms underlying the associations with cognitive impairment and LOAD require further elucidation, but both genes are interesting candidates for involvement in age-related cognitive impairment.

Objective

Carotid sinus hypersensitivity (CSH) is common in older people. The authors hypothesise that patients with CSH have a higher mortality than a geographically, age-matched older cohort.

Design

A retrospective cohort study compared to geographical and age-matched data from the Office of National Statistics.

Setting

Specialist clinic in tertiary centre.

Patients

1504 patients with CSH were identified from a single syncope outpatient assessment service between 1990 and 2001.

Interventions

Vital status was confirmed, and death certificates were sought for all deceased patients up to 2003.

Main outcome measures

Kaplan–Meier survival curves were analysed within the cohort according to three different subtypes of CSH. Standardised mortality rates (SMRs) were determined using geographical and age-matched data from the Office of National Statistics.

Results

There was no difference between CSH patients and the general population in SMRs for all causes, or for cerebrovascular or cardiovascular deaths. There was no difference in survival between the three subtypes of CSH (p=0.2) within the study cohort.

Conclusion

CSH is not associated with a higher mortality than the general population, and there are no differences in mortality between the three subtypes of CSH. This confirms earlier findings and reinforces the neutral effect of CSH on mortality.

Article summary

Article focus

Mortality rates in patients with CSH compared with age and geographically matched controls.

Mortality rates compared between the three CSH subtypes, vasodepressor, cardioinhibitory and mixed.

Key messages

This is the largest known cohort of patients with CSH to date.

This confirms previous findings by smaller studies.

CSH has no effect on mortality.

Strengths and limitations of this study

This is a retrospective study.

The sample size is large.

It was not possible to address morbidity, as there was no control group. The control group for mortality was taken from the Office of National Statistics.

Background: diagnosis of mild cognitive impairment (MCI) typically excludes individuals with medical co-morbidity. Interest in MCI screening raises the questions of what are the best criteria to identify a representative sample and what factors are associated with MCI progression to dementia.

Objectives: to compare the pattern of disease co-morbidity across different cognitive groups and to examine the role of health co-morbidity as a risk factor for dementia progression from MCI.

Methods: individuals from the MRC Cognitive Function and Ageing Study were classified as having no cognitive impairment (NCI), MCI, other cognitive impairment no dementia (OCIND) or dementia. At 2 years dementia status was assessed.

Findings: over 50% of individuals in each group reported one or more medical condition. The pattern of disease prevalence was similar in the NCI, MCI and OCIND groups. Anaemia was the only health factor associated with an increased risk of dementia progression from MCI.

Conclusion: classification of MCI using medical exclusions would exclude the majority of the population from a MCI diagnosis. This has implications for treatment decisions and clinical trial recruitment. This could not only make recruitment more difficult but also limit the generalisability of trial results. Medical co-morbidity does not help to distinguish progressive from non-progressive MCI.

The molecular pathways leading to Alzheimer-type dementia are not well understood, but the amyloid β-protein is believed to be centrally involved. The quantity of amyloid β-protein containing plaques does not correlate well with clinical status, suggesting that if amyloid β-protein is pathogenic it involves soluble non-plaque material. Using 43 brains from the Newcastle cohort of the population-representative Medical Research Council Cognitive Function and Ageing Study, we examined the relationship between biochemically distinct forms of amyloid β-protein and the presence of Alzheimer-type dementia. Cortical samples were serially extracted with Tris-buffered saline, Tris-buffered saline containing 1% TX-100 and with 88% formic acid and extracts analysed for amyloid β-protein by immunoprecipitation/western blotting. The cohort was divisible into those with dementia at death with (n = 14) or without (n = 10) significant Alzheimer-type pathology, and those who were not demented (n = 19). Amyloid β-protein monomer in extracts produced using Tris-buffered saline and Tris-buffered saline containing 1% TX-100 were strongly associated with Alzheimer type dementia (P < 0.001) and sodium dodecyl sulphate-stable amyloid β-protein dimer was detected specifically and sensitively in Tris-buffered saline, Tris-buffered saline containing 1% TX-100 and formic acid extracts of Alzheimer brain. Amyloid β-protein monomer in the formic acid fraction closely correlated with diffuse and neuritic plaque burden, but was not specific for dementia. These findings support the hypothesis that soluble amyloid β-protein is a major correlate of dementia associated with Alzheimer-type pathology and is likely to be intimately involved in the pathogenesis of cognitive failure.

Background

Deaths are rising fastest among the oldest old but data on their transitions in place of care at the end of life are scarce.

Aim

To examine the place of residence or care of ≥85 year-olds less than a year before death, and their place of death, and to map individual changes between the two.

Design of study

Population-based cohort study.

Setting

Cambridge City over-75s Cohort (CC75C) study, UK.

Method

Retrospective analysis of prospective data from males and females aged ≥85 years at death who died within a year of taking part in any CC75C survey (n = 320); death certificate linkage.

Results

Only 7% changed their address in their last year of life, yet 52% died somewhere other than their usual address at the time of death. Over two-thirds were living in the community when interviewed <1 year before death, but less than one-third who had lived at home died there (less than one-fifth in sheltered housing). Care homes were the usual address of most people dying there (77% in residential homes, 87% in nursing homes) but 15% of deaths in acute hospital came from care homes.

Conclusion

More than half the study sample of individuals of advanced old age had a change in their place of residence or care in their last year of life. These findings add weight to calls for improved end-of-life care in all settings, regardless of age, to avoid unnecessary transfers. The study data provide a baseline that can help plan and monitor initiatives to promote choice in location of care at the end of life for the very old.