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1.  Expanding Disease Definitions in Guidelines and Expert Panel Ties to Industry: A Cross-sectional Study of Common Conditions in the United States 
PLoS Medicine  2013;10(8):e1001500.
Background
Financial ties between health professionals and industry may unduly influence professional judgments and some researchers have suggested that widening disease definitions may be one driver of over-diagnosis, bringing potentially unnecessary labeling and harm. We aimed to identify guidelines in which disease definitions were changed, to assess whether any proposed changes would increase the numbers of individuals considered to have the disease, whether potential harms of expanding disease definitions were investigated, and the extent of members' industry ties.
Methods and Findings
We undertook a cross-sectional study of the most recent publication between 2000 and 2013 from national and international guideline panels making decisions about definitions or diagnostic criteria for common conditions in the United States. We assessed whether proposed changes widened or narrowed disease definitions, rationales offered, mention of potential harms of those changes, and the nature and extent of disclosed ties between members and pharmaceutical or device companies.
Of 16 publications on 14 common conditions, ten proposed changes widening and one narrowing definitions. For five, impact was unclear. Widening fell into three categories: creating “pre-disease”; lowering diagnostic thresholds; and proposing earlier or different diagnostic methods. Rationales included standardising diagnostic criteria and new evidence about risks for people previously considered to not have the disease. No publication included rigorous assessment of potential harms of proposed changes.
Among 14 panels with disclosures, the average proportion of members with industry ties was 75%. Twelve were chaired by people with ties. For members with ties, the median number of companies to which they had ties was seven. Companies with ties to the highest proportions of members were active in the relevant therapeutic area. Limitations arise from reliance on only disclosed ties, and exclusion of conditions too broad to enable analysis of single panel publications.
Conclusions
For the common conditions studied, a majority of panels proposed changes to disease definitions that increased the number of individuals considered to have the disease, none reported rigorous assessment of potential harms of that widening, and most had a majority of members disclosing financial ties to pharmaceutical companies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Health professionals generally base their diagnosis of physical and mental disorders among their patients on disease definitions and diagnostic thresholds that are drawn up by expert panels and published as statements or as part of clinical practice guidelines. These disease definitions and diagnostic thresholds are reviewed and updated in response to changes in disease detection methods, treatments, medical knowledge, and, in the case of mental illness, changes in cultural norms. Sometimes, the review process widens disease definitions and lowers diagnostic thresholds. Such changes can be beneficial. For example, they might ensure that life-threatening conditions are diagnosed early when they are still treatable. But the widening of disease definitions can also lead to over-diagnosis—the diagnosis of a condition in a healthy individual that will never cause any symptoms and won't lead to an early death. Over-diagnosis can unnecessarily label people as ill, harm healthy individuals by exposing them to treatments they do not need, and waste resources that could be used to treat or prevent “genuine” illness.
Why Was This Study Done?
In recent years, evidence for widespread financial and non-financial ties between pharmaceutical companies and the health professionals involved in writing clinical practice guidelines has increased, and concern that these links may influence professional judgments has grown. As a result, a 2011 report from the US Institute of Medicine (IOM) recommended that, whenever possible, guideline developers should not have conflicts of interest, that a minority of the panel members involved in guideline development should have conflicts of interest, and that the chairs of these panels should be free of conflicts. Much less is known, however, about the ties between industry and the health professionals involved in reviewing disease definitions and whether these ties might in some way contribute to over-diagnosis. In this cross-sectional study (an investigation that takes a snapshot of a situation at a single time point), the researchers identify panels that have recently made decisions about definitions or diagnostic thresholds for conditions that are common in the US and describe the industry ties among the panel members and the changes in disease definitions proposed by the panels.
What Did the Researchers Do and Find?
The researchers identified 16 publications in which expert panels proposed changes to the disease definitions and diagnostic criteria for 14 conditions that are common in the US such as hypertension (high blood pressure) and Alzheimer disease. The proposed changes widened the disease definition for ten diseases, narrowed it for one disease, and had an unclear impact for five diseases. Reasons included in the publications for changing disease definitions included new evidence of risk for people previously considered normal (pre-hypertension) and the emergence of new biomarkers, tests, or treatments (Alzheimer disease). Only six of the panels mentioned possible harms of the proposed changes and none appeared to rigorously assess the downsides of expanding definitions. Of the 15 panels involved in the publications (one panel produced two publications), 12 included members who disclosed financial ties to multiple companies. Notably, the commonest industrial ties among these panels were to companies marketing drugs for the disease being considered by that panel. On average, 75% of panel members disclosed industry ties (range 0% to 100%) to a median of seven companies each. Moreover, similar proportions of panel members disclosed industry ties in publications released before and after the 2011 IOM report.
What Do These Findings Mean?
These findings show that, for the conditions studied, most panels considering disease definitions and diagnostic criteria proposed changes that widened disease definitions and that financial ties with pharmaceutical companies with direct interests in the therapeutic area covered by the panel were common among panel members. Because this study does not include a comparison group, these findings do not establish a causal link between industry ties and proposals to change disease definitions. Moreover, because the study concentrates on a subset of common diseases in the US setting, the generalizability of these findings is limited. Despite these and other study limitations, these findings provide new information about the ties between industry and influential medical professionals and raise questions about the current processes of disease definition. Future research, the researchers suggest, should investigate how disease definitions change over time, how much money panel members receive from industry, and how panel proposals affect the potential market of sponsors. Finally it should aim to design new processes for reviewing disease definitions that are free from potential conflicts of interest.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001500.
A PLOS Medicine Research Article by Knüppel et al. assesses the representation of ethical issues in general clinical practice guidelines on dementia care
Wikipedia has a page on medical diagnosis (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
An article on over-diagnosis by two of the study authors is available; an international conference on preventing over-diagnosis will take place this September
The 2011 US Institute of Medicine report Clinical Practice Guidelines We Can Trust is available
A PLOS Medicine Essay by Lisa Cosgrove and Sheldon Krimsky discusses the financial ties with industry of panel members involved in the preparation of the latest revision of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM), which provides standard criteria for the classification of mental disorders
doi:10.1371/journal.pmed.1001500
PMCID: PMC3742441  PMID: 23966841
2.  Genetic susceptibility testing for neurodegenerative diseases: Ethical and practice issues 
Progress in neurobiology  2013;110:10.1016/j.pneurobio.2013.02.005.
As the genetics of neurodegenerative disease become better understood, opportunities for genetic susceptibility testing for at-risk individuals will increase. Such testing raises important ethical and practice issues related to test access, informed consent, risk estimation and communication, return of results, and policies to prevent genetic discrimination. The advent of direct-to-consumer genetic susceptibility testing for various neurodegenerative disorders (including Alzheimer’s disease, Parkinson’s disease, and certain prion diseases) means that ethical and practical challenges must be faced not only in traditional research and clinical settings, but also in broader society. This review addresses several topics relevant to the development and implementation of genetic susceptibility tests across research, clinical, and consumer settings; these include appropriate indications for testing, the implications of different methods for disclosing test results, clinical versus personal utility of risk information, psychological and behavioral responses to test results, testing of minors, genetic discrimination, and ethical dilemmas posed by whole-genome sequencing. We also identify future areas of likely growth in the field, including pharmacogenomics and genetic screening for individuals considering or engaged in activities that pose elevated risk of brain injury (e.g., football players, military personnel). APOE gene testing for risk of Alzheimer’s disease is used throughout as an instructive case example, drawing upon the authors’ experience as investigators in a series of multisite randomized clinical trials that have examined the impact of disclosing APOE genotype status to interested individuals (e.g., first-degree relatives, persons with mild cognitive impairment).
doi:10.1016/j.pneurobio.2013.02.005
PMCID: PMC3772971  PMID: 23583530
Genetic testing; risk assessment; apolipoprotein E (APOE); ethics; genetic counseling
3.  Comparing test-specific distress of susceptibility versus deterministic genetic testing for Alzheimer’s disease 
Background
Genetic risk for Alzheimer’s disease (AD) may be conferred by the susceptibility polymorphism apolipoprotein E (APOE), where the ε4 allele increases the risk of developing late-onset Alzheimer’s disease but is not a definitive predictor of the disease, or by autosomal dominant mutations (e.g., the presenilins), which almost inevitably result in early-onset familial Alzheimer’s disease. The purpose of this study was to compare the psychological impact of using these two different types of genetic information to disclose genetic risk for AD to family members of affected patients.
Methods
Data were compared from two separate protocols. The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) Study is a randomized, multi-site clinical trial that evaluated the impact of susceptibility testing for Alzheimer’s disease with APOE in 101 adult children of Alzheimer’s disease patients. A separate study, conducted at the University of Washington, assessed the impact of deterministic genetic testing by disclosing presenilin-1, presenilin-2, or TAU genotype to 22 individuals at risk for familial Alzheimer’s disease or frontotemporal dementia. In both protocols, participants received genetic counseling and completed the Impact of Event Scale (IES), a measure of test-specific distress. Scores were analyzed at the time point closest to one year post-disclosure at which IES data were available. The role of genetic test result (positive vs. negative) and type of genetic testing (deterministic vs. susceptibility) in predicting log-transformed IES scores was assessed with linear regression, controlling for age, gender, and time from disclosure.
Results
Subjects from the REVEAL Study who learned that they were positive for the susceptibility gene APOE ε4+ experienced similar, low levels of test-specific distress compared to those who received positive results of deterministic testing in the University of Washington study (p= 0.78). APOE ε4+ individuals in the susceptibility protocol experienced more test-specific distress than those who tested ε4− in the same study (p= 0.04); however, among those receiving deterministic test disclosure, the subjects who received positive results did not experience significantly higher levels of distress when compared to those who received negative results (p= 0.88).
Conclusions
The findings of this preliminary study, with limited sample size, suggest that the test-related distress experienced by those receiving positive results for a deterministic mutation is similar to the distress experienced by those receiving positive results from genetic susceptibility testing, and that the majority of participants receiving genotype disclosure do not experience clinically significant distress as indicated by IES scores one year after learning of their test results.
doi:10.1016/j.jalz.2008.04.007
PMCID: PMC2610442  PMID: 19012865
genetic susceptibility testing; deterministic testing; Alzheimer’s disease; APOE; genetic counseling
4.  Cardiovascular and Cerebrovascular Events in the Randomized, Controlled Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) 
PLoS Clinical Trials  2006;1(7):e33.
Objectives:
The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was designed to evaluate the conventional NSAID naproxen sodium and the selective COX-2 inhibitor celecoxib for primary prevention of Alzheimer's dementia (AD). On 17 December 2004, after the Adenoma Prevention with Celecoxib (APC) trial reported increased cardiovascular risks with celecoxib, the ADAPT Steering Committee suspended treatment and enrollment. This paper reports on cardiovascular and cerebrovascular events in ADAPT.
Design:
ADAPT is a randomized, placebo-controlled, parallel chemoprevention trial with 1–46 mo of follow-up.
Setting:
The trial was conducted at six field sites in the United States: Baltimore, Maryland; Boston, Massachusetts; Rochester, New York; Seattle, Washington; Sun City, Arizona; and Tampa, Florida.
Participants:
The 2,528 participants were aged 70 y and older with a family history of AD.
Interventions:
Study treatments were celecoxib (200 mg b.i.d.), naproxen sodium (220 mg b.i.d.), and placebo.
Outcome measures:
Outcome measures were deaths, along with nonfatal myocardial infarction (MI), stroke, congestive heart failure (CHF), transient ischemic attack (TIA), and antihypertensive treatment recorded from structured interviews at scheduled intervals. Cox proportional hazards regression was used to analyze these events individually and in several composites.
Results:
Counts (with 3-y incidence) of participants who experienced cardiovascular or cerebrovascular death, MI, stroke, CHF, or TIA in the celecoxib-, naproxen-, and placebo-treated groups were 28/717 (5.54%), 40/713 (8.25%), and 37/1070 (5.68%), respectively. This yielded a hazard ratio (95% confidence interval [CI]) for celecoxib of 1.10 (0.67–1.79) and for naproxen of 1.63 (1.04–2.55). Antihypertensive treatment was initiated in 160/440 (47.43%), 147/427 (45.00%), and 164/644 (34.08%). This yielded hazard ratios (CIs) of 1.56 for celecoxib (1.26–1.94) and 1.40 for naproxen (1.12–1.75).
Conclusions:
For celecoxib, ADAPT data do not show the same level of risk as those of the APC trial. The data for naproxen, although not definitive, are suggestive of increased cardiovascular and cerebrovascular risk.
Editorial Commentary
Background: Evidence from observational studies suggests that people taking certain nonsteroidal anti-inflammatory drugs (NSAIDs) are at lower risk of developing Alzheimer's disease. However, in order to reliably find out whether NSAIDs reduce the risk of Alzheimer's, it is important to perform a properly designed randomized trial. Such a trial, ADAPT, was sponsored by the United States National Institute on Aging, and the study started recruitment in 2001. The trial involved three treatment arms: naproxen (one type of NSAID), celecoxib (another type of NSAID, but one that specifically inhibits an enzyme called COX-2), and placebo, acting as a control. It was planned that 2,625 participants would be recruited and that the primary outcome of interest was incidence of Alzheimer's disease in the three treatment arms; the trial would run for 7 y. However, this trial was terminated early, a decision based in part on information from other studies that demonstrated an increased risk of certain harms, such as heart attacks and strokes, in people taking celecoxib and other types of COX-2 inhibitors. Therefore meaningful data were not available at the time on the study's primary outcome (prevention of Alzheimer's disease). However, data about the chance of these harms are available from the ADAPT results, and these results are presented here.
What this trial shows: The investigators compared frequency of particular types of harm in the treatment arms: heart attack, stroke, congestive heart failure (CHF), and transient ischemic attack (TIA). For each individual type of event, some were more likely in people treated with celecoxib compared with placebo, but others were not. When considering people taking naproxen, all four types of adverse events were more likely to occur in the treatment group as compared to placebo. The investigators then combined data from all four types of harm together, and here they found that the overall risk in people taking celecoxib was higher than for people taking placebo, but that this was not statistically significant, so it could have been due to chance alone. When considering naproxen as compared with placebo, the researchers saw an approximately 60% increase in risk for all four harms combined, and this result was statistically significant. The death rate in people taking either celecoxib or naproxen was higher than for those taking placebo, but this was not statistically significant, and therefore could have been due to chance.
Strengths and limitations: Strengths of this study include the randomization procedures, which used a distributed computer system to assign patients to treatment arms (minimizing the chance of bias), blinding of patients to their treatment assignment, and blinding of the committee reviewing deaths and safety reports to treatment assignment. One limitation is that although the trial was large and appropriately powered for the main outcome (prevention of Alzheimer's disease), the number of safety events reported here were small and the trial was not primarily designed to examine safety. Further, participants eligible to join this trial were required to have a family history of Alzheimer's disease, so it is possible that their risk factors are slightly different from the general population.
Contribution to the evidence: The cardiovascular safety of NSAID's, including COX-2 inhibitors, is an intensely debated topic. Very few published data exist on the long-term safety of celecoxib as compared with placebo, although there are a number of as-yet-unpublished studies. These data on harms provided by ADAPT provide important results that should be incorporated into future meta-analyses. Such meta-analyses will give a more rigorous and reliable assessment of the safety of the drugs studied here.
doi:10.1371/journal.pctr.0010033
PMCID: PMC1851724  PMID: 17111043
5.  Genetic Predisposition to Increased Blood Cholesterol and Triglyceride Lipid Levels and Risk of Alzheimer Disease: A Mendelian Randomization Analysis 
PLoS Medicine  2014;11(9):e1001713.
In this study, Proitsi and colleagues use a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset Alzheimer's Disease (LOAD) and find that genetic predisposition to increased plasma cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk.
Please see later in the article for the Editors' Summary
Background
Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.
Methods and Findings
We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n = 10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p<5×10−8 and trait specific scores using SNPs associated exclusively with each trait at p<5×10−8 were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR] = 1.005, 95% CI 0.82–1.24, p = 0.962 per 1 unit increase in HDL-c; OR = 0.901, 95% CI 0.65–1.25, p = 0.530 per 1 unit increase in LDL-c; OR = 1.104, 95% CI 0.89–1.37, p = 0.362 per 1 unit increase in triglycerides; and OR = 0.954, 95% CI 0.76–1.21, p = 0.688 per 1 unit increase in total cholesterol). Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance.
Conclusions
Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 44 million people worldwide have dementia, a group of brain disorders characterized by an irreversible decline in memory, communication, and other “cognitive” functions. Dementia mainly affects older people and, because people are living longer, experts estimate that more than 135 million people will have dementia by 2050. The commonest form of dementia is Alzheimer disease. In this type of dementia, protein clumps called plaques and neurofibrillary tangles form in the brain and cause its degeneration. The earliest sign of Alzheimer disease is usually increasing forgetfulness. As the disease progresses, affected individuals gradually lose their ability to deal with normal daily activities such as dressing. They may become anxious or aggressive or begin to wander. They may also eventually lose control of their bladder and of other physical functions. At present, there is no cure for Alzheimer disease although some of its symptoms can be managed with drugs. Most people with the disease are initially cared for at home by relatives and other unpaid carers, but many patients end their days in a care home or specialist nursing home.
Why Was This Study Done?
Several lines of evidence suggest that lipid metabolism (how the body handles cholesterol and other fats) is altered in patients whose Alzheimer disease develops after the age of 60 years (late onset Alzheimer disease, LOAD). In particular, epidemiological studies (observational investigations that examine the patterns and causes of disease in populations) have found an association between high amounts of cholesterol in the blood in midlife and the risk of LOAD. However, observational studies cannot prove that abnormal lipid metabolism (dyslipidemia) causes LOAD. People with dyslipidemia may share other characteristics that cause both dyslipidemia and LOAD (confounding) or LOAD might actually cause dyslipidemia (reverse causation). Here, the researchers use “Mendelian randomization” to examine whether lifetime changes in lipid metabolism caused by genes have a causal impact on LOAD risk. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if dyslipidemia causes LOAD, genetic variants that affect lipid metabolism should be associated with an altered risk of LOAD.
What Did the Researchers Do and Find?
The researchers investigated whether genetic predisposition to raised lipid levels increased the risk of LOAD in 10,578 participants (3,914 patients with LOAD, 1,675 elderly people without LOAD, and 4,989 population controls) using data collected in six genome wide studies looking for gene variants associated with Alzheimer disease. The researchers constructed a genotype risk score (GRS) for each participant using genetic risk markers for four types of blood lipids on the basis of the presence of single nucleotide polymorphisms (SNPs, a type of gene variant) in their DNA. When the researchers used statistical methods to investigate the association between the GRS and LOAD among all the study participants, they found no association between the GRS and LOAD.
What Do These Findings Mean?
These findings suggest that the genetic predisposition to raised blood levels of four types of lipid is not causally associated with LOAD risk. The accuracy of this finding may be affected by several limitations of this study, including the small proportion of lipid variance explained by the GRS and the validity of several assumptions that underlie all Mendelian randomization studies. Moreover, because all the participants in this study were white, these findings may not apply to people of other ethnic backgrounds. Given their findings, the researchers suggest that the observed epidemiological associations between abnormal lipid levels in the blood and variation in lipid levels for reasons other than genetics, or to LOAD risk could be secondary to variation in lipid levels for reasons other than genetics, or to LOAD, a possibility that can be investigated by studying blood lipid levels and other markers of lipid metabolism over time in large groups of patients with LOAD. Importantly, however, these findings provide new information about the role of lipids in LOAD development that may eventually lead to new therapeutic and public-health interventions for Alzheimer disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001713.
The UK National Health Service Choices website provides information (including personal stories) about Alzheimer's disease
The UK not-for-profit organization Alzheimer's Society provides information for patients and carers about dementia, including personal experiences of living with Alzheimer's disease
The US not-for-profit organization Alzheimer's Association also provides information for patients and carers about dementia and personal stories about dementia
Alzheimer's Disease International is the international federation of Alzheimer disease associations around the world; it provides links to individual associations, information about dementia, and links to World Alzheimer Reports
MedlinePlus provides links to additional resources about Alzheimer's disease (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001713
PMCID: PMC4165594  PMID: 25226301
6.  Using Alzheimer’s disease as a model for genetic risk disclosure: Implications for personal genomics 
Clinical Genetics  2011;80(5):407-414.
Susceptibility testing for common, complex adult-onset diseases is projected to become more commonplace as the rapid pace of genomic discoveries continues, and evidence regarding the potential benefits and harms of such testing is needed to inform medical practice and health policy. Apolipoprotein E (APOE) testing for risk of Alzheimer’s disease (AD) provides a paradigm in which to examine the process and impact of disclosing genetic susceptibility for a prevalent, severe and incurable neurological condition. This review summarizes findings from a series of multi-site randomized clinical trials examining psychological and behavioral responses to various methods of genetic risk assessment for AD using APOE disclosure. We discuss challenges involved in disease risk estimation and communication and the extent to which participants comprehend and perceive utility in their genetic risk information. Findings on the psychological impact of test results are presented (e.g., distress), along with data on participants’ health behavior and insurance purchasing responses (e.g., long term care). Finally, we report comparisons of the safety and efficacy of intensive genetic counseling approaches to briefer models that emphasize streamlined processes and educational materials. The implications of these findings for the emerging field of personal genomics are discussed, with directions identified for future research.
doi:10.1111/j.1399-0004.2011.01739.x
PMCID: PMC3191239  PMID: 21696382
7.  Development of a Communication Protocol for Telephone Disclosure of Genetic Test Results for Cancer Predisposition 
JMIR Research Protocols  2014;3(4):e49.
Background
Dissemination of genetic testing for disease susceptibility, one application of “personalized medicine”, holds the potential to empower patients and providers through informed risk reduction and prevention recommendations. Genetic testing has become a standard practice in cancer prevention for high-risk populations. Heightened consumer awareness of “cancer genes” and genes for other diseases (eg, cardiovascular and Alzheimer’s disease), as well as the burgeoning availability of increasingly complex genomic tests (ie, multi-gene, whole-exome and -genome sequencing), has escalated interest in and demand for genetic risk assessment and the specialists who provide it. Increasing demand is expected to surpass access to genetic specialists. Thus, there is urgent need to develop effective and efficient models of delivery of genetic information that comparably balance the risks and benefits to the current standard of in-person communication.
Objective
The aim of this pilot study was to develop and evaluate a theoretically grounded and rigorously developed protocol for telephone communication of BRCA1/2 (breast cancer) test results that might be generalizable to genetic testing for other hereditary cancer and noncancer syndromes.
Methods
Stakeholder data, health communication literature, and our theoretical model grounded in Self-Regulation Theory of Health Behavior were used to develop a telephone communication protocol for the communication of BRCA1/2 genetic test results. Framework analysis of selected audiotapes of disclosure sessions and stakeholders’ feedback were utilized to evaluate the efficacy and inform refinements to this protocol.
Results
Stakeholder feedback (n=86) and audiotapes (38%, 33/86) of telephone disclosures revealed perceived disadvantages and challenges including environmental factors (eg, non-private environment), patient-related factors (eg, low health literacy), testing-related factors (eg, additional testing needed), and communication factors (eg, no visual cues). Resulting modifications to the communication protocol for BRCA1/2 test results included clarified patient instructions, scheduled appointments, refined visual aids, expanded disclosure checklist items, and enhanced provider training.
Conclusions
Analyses of stakeholders’ experiences and audiotapes of telephone disclosure of BRCA1/2 test results informed revisions to communication strategies and a protocol to enhance patient outcomes when utilizing telephone to disclose genetic test results.
doi:10.2196/resprot.3337
PMCID: PMC4259920  PMID: 25355401
genetic testing; test result disclosure; communication; telemedicine; cancer risk assessment; self-regulation theory of health behavior
8.  Dementia 
Clinical Evidence  2012;2012:1001.
Introduction
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments on cognitive symptoms of dementia (Alzheimer's, Lewy body, or vascular)? What are the effects of treatments on behavioural and psychological symptoms of dementia (Alzheimer's, Lewy body, or vascular)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 49 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine), antidepressants (clomipramine, fluoxetine, imipramine, sertraline), antipsychotics (haloperidol, olanzapine, quetiapine, risperidone), aromatherapy, benzodiazepines (diazepam, lorazepam), cognitive behavioural therapy (CBT), cognitive stimulation, exercise, ginkgo biloba, memantine, mood stabilisers (carbamazepine, sodium valproate/valproic acid), music therapy, non-steroidal anti-inflammatory drugs (NSAIDs), omega 3 (fish oil), reminiscence therapy, and statins.
Key Points
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
Median life expectancy for people with Alzheimer's and Lewy body dementia is about 6 years after diagnosis, although many people may live far longer.
RCTs of dementia are often not representative of all people with dementia; most are of 6 months' duration or less, not in primary care, and in people with Alzheimer's disease. Few RCTs address vascular dementia, and fewer still Lewy body dementia.
Some cognitive symptoms of dementia may be improved by acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine). Acetylcholinesterase inhibitors may improve cognitive function and global function scores compared with placebo at 12 to 26 weeks in people with Alzheimer's disease. However, they may be associated with an increase in adverse effects, particularly GI symptoms (anorexia, nausea, vomiting, or diarrhoea).
We don't know whether cognitive stimulation, music therapy, reminiscence therapy, omega 3 fish oil, statins, or NSAIDs are effective at improving cognitive outcomes in people with cognitive symptoms of dementia, as we found insufficient evidence.
In people with cognitive symptoms, memantine may modestly improve cognitive function and global function scores in people with Alzheimer's disease over 24 to 28 weeks, and may modestly improve activities of daily living scores in people with moderate to severe Alzheimer's disease. Although memantine is associated with a statistically significant increase in cognition scores in some population groups, the clinical importance of some of these results is unclear.
We found inconsistent evidence on the effects of ginkgo biloba on cognitive outcomes, which varied by the analysis performed. We found no evidence that ginkgo biloba improves activities of daily living outcomes, but the available evidence was weak.
Acetylcholinesterase inhibitors may marginally improve neuropsychiatric symptoms compared with placebo in people with behavioural and psychological symptoms of dementia, but they are also associated with adverse effects.
We don't know whether antidepressants (clomipramine, fluoxetine, imipramine, sertraline) improve depressive symptoms in people with Alzheimer's disease associated with depression. Many RCTs were small and short term, and adverse effects were sparsely reported.
Memantine may be associated with a small improvement in neuropsychiatric symptoms compared with placebo in people with behavioural and psychological symptoms of dementia, but it is also associated with adverse effects.
We don't know whether diazepam, lorazepam, aromatherapy, CBT, exercise, carbamazepine, or sodium valproate/valproic acid are effective at improving neuropsychiatric symptoms in people with behavioural and psychological symptoms of dementia, as we found insufficient evidence.
Some antipsychotics may improve neuropsychiatric symptoms or aggression in people with behavioural and psychological symptoms of dementia, but antipsychotics are also associated with an increased risk of severe adverse events such as stroke, TIA, or death.
CAUTION: Regulatory bodies have issued alerts that both conventional and atypical antipsychotics are associated with an increased risk of death in older people treated for dementia-related psychosis.
PMCID: PMC3437526  PMID: 23870856
9.  Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors 
Genetics in Medicine  2011;13(6):597-605.
Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10–12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apoli-poprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD.
doi:10.1097/GIM.0b013e31821d69b8
PMCID: PMC3326653  PMID: 21577118
Alzheimer disease; dementia; guideline; genetic testing; genetic counseling
10.  Dementia 
Clinical Evidence  2010;2010:1001.
Introduction
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments on cognitive symptoms of dementia (Alzheimer's, Lewy body, or vascular)? What are the effects of treatments on behavioural and psychological symptoms of dementia (Alzheimer's, Lewy body, or vascular)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine), antidepressants (clomipramine, fluoxetine, imipramine, sertraline), antipsychotics (haloperidol, olanzapine, quetiapine, risperidone), aromatherapy, benzodiazepines (diazepam, lorazepam), cognitive behavioural therapy (CBT), cognitive stimulation, exercise, ginkgo biloba, memantine, mood stabilisers (carbamazepine, sodium valproate/valproic acid), music therapy, non-steroidal anti-inflammatory drugs (NSAIDs), omega 3 (fish oil), reminiscence therapy, and statins.
Key Points
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
Median life expectancy for people with Alzheimer's and Lewy body dementia is about 6 years after diagnosis, although many people may live far longer.
RCTs of dementia are often not representative of all people with dementia; most are 6 months or less, not in primary care, and most RCTs are in people with Alzheimer's disease. There are fewer RCTs in people with vascular dementia, and fewer still in people with Lewy body dementia.
Cognitive symptoms of dementia can be improved by acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine). Acetylcholinesterase inhibitors seem to improve cognitive function, global state, and activities of daily living scores compared with placebo at 26 weeks in people with Alzheimer's disease.However, they may be associated with an increase in adverse effects, particularly GI symptoms (anorexia, nausea, vomiting, or diarrhoea).
We don't know whether cognitive stimulation, music therapy, reminiscence therapy, omega 3 fish oil, statins, or NSAIDs are effective at improving cognitive outcomes in people with cognitive symptoms of dementia, as we found insufficient evidence.
In people with cognitive symptoms, memantine may improve global state and activities of daily living scores in people with moderate to severe Alzheimer's disease over 24 to 28 weeks, but we don't know about these in mild to moderate Alzheimer's disease. Although memantine is associated with a statistically significant increase in cognition scores in some population groups, the clinical importance of these results is unclear.
Ginkgo biloba is unlikely to improve cognitive function in people with Alzheimer's disease or vascular dementia. However, evidence is of poor quality so this conclusion should be interpreted with caution.
Acetylcholinesterase inhibitors may marginally improve neuropsychiatric symptoms compared with placebo in people with behavioural and psychological symptoms of dementia, but they are also associated with adverse effects.
Antidepressants (clomipramine, fluoxetine, imipramine, sertraline) may improve depressive symptoms compared with placebo in people with Alzheimer's disease associated with depression. However, RCTs were small and short term, and adverse effects were sparsely reported.
Memantine may be associated with a small improvement in neuropsychiatric symptoms compared with placebo in people with behavioural and psychological symptoms of dementia, but it is also associated with adverse effects.
We don't know whether diazepam, lorazepam, aromatherapy, CBT, exercise, carbamazepine, or sodium valproate/valproic acid are effective at improving neuropsychiatric symptoms in people with behavioural and psychological symptoms of dementia, as we found insufficient evidence.
Some antipsychotics may improve neuropsychiatric symptoms or aggression in people with behavioural and psychological symptoms of dementia, but antipsychotics are also associated with an increase risk of severe adverse events such as stroke, TIA, or death.
CAUTION: Regulatory bodies have issued alerts that both conventional and atypical antipsychotics are associated with an increased risk of death in elderly people treated for dementia-related psychosis.
PMCID: PMC2907611  PMID: 21726471
11.  Prevalence, Distribution, and Impact of Mild Cognitive Impairment in Latin America, China, and India: A 10/66 Population-Based Study 
PLoS Medicine  2012;9(2):e1001170.
A set of cross-sectional surveys carried out in Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India reveal the prevalence and between-country variation in mild cognitive impairment at a population level.
Background
Rapid demographic ageing is a growing public health issue in many low- and middle-income countries (LAMICs). Mild cognitive impairment (MCI) is a construct frequently used to define groups of people who may be at risk of developing dementia, crucial for targeting preventative interventions. However, little is known about the prevalence or impact of MCI in LAMIC settings.
Methods and Findings
Data were analysed from cross-sectional surveys established by the 10/66 Dementia Research Group and carried out in Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India on 15,376 individuals aged 65+ without dementia. Standardised assessments of mental and physical health, and cognitive function were carried out including informant interviews. An algorithm was developed to define Mayo Clinic amnestic MCI (aMCI). Disability (12-item World Health Organization disability assessment schedule [WHODAS]) and informant-reported neuropsychiatric symptoms (neuropsychiatric inventory [NPI-Q]) were measured. After adjustment, aMCI was associated with disability, anxiety, apathy, and irritability (but not depression); between-country heterogeneity in these associations was only significant for disability. The crude prevalence of aMCI ranged from 0.8% in China to 4.3% in India. Country differences changed little (range 0.6%–4.6%) after standardization for age, gender, and education level. In pooled estimates, aMCI was modestly associated with male gender and fewer assets but was not associated with age or education. There was no significant between-country variation in these demographic associations.
Conclusions
An algorithm-derived diagnosis of aMCI showed few sociodemographic associations but was consistently associated with higher disability and neuropsychiatric symptoms in addition to showing substantial variation in prevalence across LAMIC populations. Longitudinal data are needed to confirm findings—in particular, to investigate the predictive validity of aMCI in these settings and risk/protective factors for progression to dementia; however, the large number affected has important implications in these rapidly ageing settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, more than 35 million people worldwide have dementia, a group of brain disorders characterized by an irreversible decline in memory, problem solving, communication, and other “cognitive” functions. Dementia, the commonest form of which is Alzheimer's disease, mainly affects older people and, because more people than ever are living to a ripe old age, experts estimate that, by 2050, more than 115 million people will have dementia. At present, there is no cure for dementia although drugs can be used to manage some of the symptoms. Risk factors for dementia include physical inactivity, infrequent participation in mentally or socially stimulating activities, and common vascular risk factors such as high blood pressure, diabetes, and smoking. In addition, some studies have reported that mild cognitive impairment (MCI) is associated with an increased risk of dementia. MCI can be seen as an intermediate state between normal cognitive aging (becoming increasingly forgetful) and dementia although many people with MCI never develop dementia, and some types of MCI can be static or self-limiting. Individuals with MCI have cognitive problems that are more severe than those normally seen in people of a similar age but they have no other symptoms of dementia and are able to look after themselves. The best studied form of MCI—amnestic MCI (aMCI)—is characterized by memory problems such as misplacing things and forgetting appointments.
Why Was This Study Done?
Much of the expected increase in dementia will occur in low and middle income countries (LAMICs) because these countries have rapidly aging populations. Given that aMCI is frequently used to define groups of people who may be at risk of developing dementia, it would be useful to know what proportion of community-dwelling older adults in LAMICs have aMCI (the prevalence of aMCI). Such information might help governments plan their future health care and social support needs. In this cross-sectional, population-based study, the researchers estimate the prevalence of aMCI in eight LAMICs using data collected by the 10/66 Dementia Research Group. They also investigate the association of aMCI with sociodemographic factors (for example, age, gender, and education), disability, and neuropsychiatric symptoms such as anxiety, apathy, irritability, and depression. A cross-sectional study collects data on a population at a single time point; the 10/66 Dementia Research Group is building an evidence base to inform the development and implementation of policies for improving the health and social welfare of older people in LAMICs, particularly people with dementia.
What Did the Researchers Do and Find?
In cross-sectional surveys carried out in six Latin American LAMICS, China, and India, more than 15,000 elderly individuals without dementia completed standardized assessments of their mental and physical health and their cognitive function. Interviews with relatives and carers provided further details about the participant's cognitive decline and about neuropsychiatric symptoms. The researchers developed an algorithm (set of formulae) that used the data collected in these surveys to diagnose aMCI in the study participants. Finally, they used statistical methods to analyze the prevalence, distribution, and impact of aMCI in the eight LAMICs. The researchers report that aMCI was associated with disability, anxiety, apathy, and irritability but not with depression and that the prevalence of aMCI ranged from 0.8% in China to 4.3% in India. Other analyses show that, considered across all eight countries, aMCI was modestly associated with being male (men had a slightly higher prevalence of aMCI than women) and with having fewer assets but was not associated with age or education.
What Do These Findings Mean?
These findings suggest that aMCI, as diagnosed using the algorithm developed by the researchers, is consistently associated with higher disability and with neuropsychiatric symptoms in the LAMICs studied but not with most sociodemographic factors. Because prevalidated and standardized measurements were applied consistently in all the countries and a common algorithm was used to define aMCI, these findings also suggest that the prevalence of aMCI varies markedly among LAMIC populations and is similar to or slightly lower than the prevalence most often reported for European and North American populations. Although longitudinal studies are now needed to investigate the extent to which aMCI can be used as risk marker for further cognitive decline and dementia in these settings, the large absolute numbers of older people with aMCI in LAMICs revealed here potentially has important implications for health care and social service planning in these rapidly aging and populous regions of the world.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001170.
Alzheimer's Disease International is the international federation of Alzheimer associations around the world; it provides links to individual associations, information about dementia, and links to three World Alzheimer Reports; information about the 10/66 Dementia Research Group is also available on this web site
The Alzheimer's Society provides information for patients and carers about dementia, including information on MCI and personal stories about living with dementia
The Alzheimer's Association also provides information for patients and carers about dementia and about MCI, and personal stories about dementia
A BBC radio program that includes an interview with a man with MCI is available
MedlinePlus provides links to further resources about MCI and dementia (in English and Spanish)
doi:10.1371/journal.pmed.1001170
PMCID: PMC3274506  PMID: 22346736
12.  Reducing Amyloid Plaque Burden via Ex Vivo Gene Delivery of an Aβ-Degrading Protease: A Novel Therapeutic Approach to Alzheimer Disease 
PLoS Medicine  2007;4(8):e262.
Background
Understanding the mechanisms of amyloid-β protein (Aβ) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Aβ levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain Aβ in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce Aβ levels in AD. The objective of this study was to determine if enhancing the clearance of Aβ in the brain by ex vivo gene delivery of an Aβ-degrading protease can reduce amyloid plaque burden.
Methods and Findings
We generated a secreted form of the Aβ-degrading protease neprilysin, which significantly lowers the levels of naturally secreted Aβ in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of β-amyloid precursor protein (APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment (72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site (34% reduction, p = 0.0020; and 55% reduction, p = 0.0081, respectively).
Conclusions
Ex vivo gene delivery of an Aβ-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of Aβ-degrading proteases as a means to therapeutically lower Aβ levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.
Matthew Hemming and colleagues describe the ex vivo gene delivery of an Aβ-degrading protease that reduces amyloid plaque burden in transgenic mice expressing human amyloid precursor protein.
Editors' Summary
Background.
Alzheimer disease is the most common form of dementia and is increasingly common as people age. It may affect up to half of the population in people over 85 years of age. The classic pathological features of Alzheimer disease in the brain were described 100 years ago by a German neuropathologist, Alois Alzheimer. They consist of plaques, which are made up of a protein called amyloid-β protein (shortened to Aβ); and tangles of another protein, called tau. These proteins accumulate especially in areas of the brain where memory and thought are processed and are believed to be toxic to neurons. There are a number of inherited forms of Alzheimer disease which are caused by mutations either in the protein from which Aβ is derived, called beta-amyloid precursor protein (shortened to APP) or in other proteins that act to release the Aβ protein from APP. Research on these inherited forms of Alzheimer disease has helped in the understanding of how plaques accumulate, which has subsequently led to new potential approaches to the treatment of Alzheimer disease such as lowering the production of Aβ from APP or enhancing clearance of the plaques.
Why Was This Study Done?
The researchers here wanted to investigate the use of a type of gene therapy called ex vivo (which means out of body) gene therapy, in which cells are taken from an individual, genetically altered, then put back into the individual they were taken from. This approach has already been studied in some human diseases and conditions including hemophilia, cancer, and spinal cord injury. The researchers here wanted to investigate whether they could use this approach to deliver to the brain one of the proteases that breaks down amyloid plaques.
What Did the Researchers Do and Find?
The researchers used a mouse model of Alzheimer disease in which, as the mice age, they develop plaques in the brain made of the same protein found in human Alzheimer disease. The researchers took a particular type of cell from the mice called a fibroblast, used a virus called a lentivirus to insert into the cells a protease called neprilysin that can degrade Aβ, and then injected these altered cells into the brains of the mice. They then compared results of these experiments with what happened when cells with a control (an inactive virus) were injected. They found that when the active protease was put into the brains of mice there was a substantial clearing of plaques especially in the areas close to the injection site, compared with the control mice.
What Do These Findings Mean?
These results suggest that this ex vivo gene therapy approach to Alzheimer disease is worth considering further. However, despite showing that the plaques were cleared the researchers did not show whether or not there was any effect on the behavior of the mice, i.e., whether there was any effect on the symptoms that the plaques cause. In addition, before this approach could be used in humans more work would need to be done, including showing that the lentivirus and the protease used were safe in humans, and the injection could be scaled up to the much larger human brain.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040262.
The slides from the original cases that Alois Alzheimer described are available online
Current research is discussed by the Alzheimer Research Forum
News and information for researchers, doctors, and patients, including a 24-hour help line, are available from the Alzheimer's Association
Medline Plus, the health information site for patients from the US National Library of Medicine, has a page of links on Alzheimer disease
The US National Institutes of Health National Institute of Aging has a fact sheet on Alzheimer disease, which is also available in Spanish
The UK's National Health Service online information site has information on Alzheimer disease
doi:10.1371/journal.pmed.0040262
PMCID: PMC1952204  PMID: 17760499
13.  A data-driven model of biomarker changes in sporadic Alzheimer's disease 
Brain  2014;137(9):2564-2577.
Young et al. reformulate an event-based model for the progression of Alzheimer's disease to make it applicable to a heterogeneous sporadic disease population. The enhanced model predicts the ordering of biomarker abnormality in sporadic Alzheimer's disease independently of clinical diagnoses or biomarker cut-points, and shows state-of-the-art diagnostic classification performance.
We demonstrate the use of a probabilistic generative model to explore the biomarker changes occurring as Alzheimer’s disease develops and progresses. We enhanced the recently introduced event-based model for use with a multi-modal sporadic disease data set. This allows us to determine the sequence in which Alzheimer’s disease biomarkers become abnormal without reliance on a priori clinical diagnostic information or explicit biomarker cut points. The model also characterizes the uncertainty in the ordering and provides a natural patient staging system. Two hundred and eighty-five subjects (92 cognitively normal, 129 mild cognitive impairment, 64 Alzheimer’s disease) were selected from the Alzheimer’s Disease Neuroimaging Initiative with measurements of 14 Alzheimer’s disease-related biomarkers including cerebrospinal fluid proteins, regional magnetic resonance imaging brain volume and rates of atrophy measures, and cognitive test scores. We used the event-based model to determine the sequence of biomarker abnormality and its uncertainty in various population subgroups. We used patient stages assigned by the event-based model to discriminate cognitively normal subjects from those with Alzheimer’s disease, and predict conversion from mild cognitive impairment to Alzheimer’s disease and cognitively normal to mild cognitive impairment. The model predicts that cerebrospinal fluid levels become abnormal first, followed by rates of atrophy, then cognitive test scores, and finally regional brain volumes. In amyloid-positive (cerebrospinal fluid amyloid-β1–42 < 192 pg/ml) or APOE-positive (one or more APOE4 alleles) subjects, the model predicts with high confidence that the cerebrospinal fluid biomarkers become abnormal in a distinct sequence: amyloid-β1–42, phosphorylated tau, total tau. However, in the broader population total tau and phosphorylated tau are found to be earlier cerebrospinal fluid markers than amyloid-β1–42, albeit with more uncertainty. The model’s staging system strongly separates cognitively normal and Alzheimer’s disease subjects (maximum classification accuracy of 99%), and predicts conversion from mild cognitive impairment to Alzheimer’s disease (maximum balanced accuracy of 77% over 3 years), and from cognitively normal to mild cognitive impairment (maximum balanced accuracy of 76% over 5 years). By fitting Cox proportional hazards models, we find that baseline model stage is a significant risk factor for conversion from both mild cognitive impairment to Alzheimer’s disease (P = 2.06 × 10−7) and cognitively normal to mild cognitive impairment (P = 0.033). The data-driven model we describe supports hypothetical models of biomarker ordering in amyloid-positive and APOE-positive subjects, but suggests that biomarker ordering in the wider population may diverge from this sequence. The model provides useful disease staging information across the full spectrum of disease progression, from cognitively normal to mild cognitive impairment to Alzheimer’s disease. This approach has broad application across neurodegenerative disease, providing insights into disease biology, as well as staging and prognostication.
doi:10.1093/brain/awu176
PMCID: PMC4132648  PMID: 25012224
event-based model; disease progression; Alzheimer’s disease; biomarkers; biomarker ordering
14.  Psychosocial Factors That Shape Patient and Carer Experiences of Dementia Diagnosis and Treatment: A Systematic Review of Qualitative Studies 
PLoS Medicine  2012;9(10):e1001331.
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
doi:10.1371/journal.pmed.1001331
PMCID: PMC3484131  PMID: 23118618
15.  Harm Avoidance and Risk of Alzheimer’s Disease 
Psychosomatic Medicine  2011;73(8):690-696.
Objective
To test the hypothesis that harm avoidance, a trait associated with behavioral inhibition, is associated with risk of developing Alzheimer’s disease.
Methods
A total of 791 adults aged 55 years and older without dementia completed a standard self report measure of harm avoidance. They then underwent annual evaluations that included detailed cognitive testing and clinical classification of mild cognitive impairment, dementia and Alzheimer’s disease. In a uniform neuropathologic examination of those who died, counts of neuritic plaques diffuse plaques, and neurofibrillary tangles were standardized and combined to yield a pathologic measure of disease. The relation of harm avoidance to incidence of Alzheimer’s disease and related outcomes was estimated in analyses adjusted for age, sex, and education.
Results
During a mean of 3.5 years of annual observation, 98 people (12.4%) developed incident Alzheimer’s disease. High level of harm avoidance (90th percentile) was associated with a more than twofold increase in risk of Alzheimer’s disease compared to a low score (10th percentile). Higher harm avoidance was also associated with increased incidence of mild cognitive impairment and more rapid decline in episodic memory, working memory, and perceptual speed (but not semantic memory or visuospatial ability). In 116 participants who died and underwent brain autopsy, harm avoidance was not related to a composite measure of plaques and tangles.
Conclusion
High level of the harm avoidance trait, indicating a tendency toward behavioral inhibition, is related to risk of developing Alzheimer’s disease and its precursor, mild cognitive impairment.
doi:10.1097/PSY.0b013e3182302ale
PMCID: PMC3304581  PMID: 21949425
Harm avoidance; Alzheimer’s disease; mild cognitive impairment; cognitive decline; longitudinal studies; brain autopsy
16.  Cholinesterase Inhibitors in Mild Cognitive Impairment: A Systematic Review of Randomised Trials 
PLoS Medicine  2007;4(11):e338.
Background
Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia.
Methods and Findings
The terms “donepezil”, “rivastigmine”, “galantamine”, and “mild cognitive impairment” and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64–1.12), and 0.84 (0.57–1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain).
Conclusions
The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.
A systematic review of trials of cholinesterase inhibitors for preventing transition of mild cognitive impairment (MCI) to dementia, conducted by Roberto Raschetti and colleagues, found no difference between treatment and control groups and concluded that uncertainty regarding the definition of MCI casts doubts on the validity of such trials.
Editors' Summary
Background.
Worldwide, more than 24 million people have dementia, a group of brain disorders characterized by an irreversible decline in memory, problem solving, communication, and other “cognitive” functions. The commonest form of dementia is Alzheimer disease (AD). The risk of developing AD increases with age—AD is rare in people younger than 65 but about half of people over 85 years old have it. The earliest symptom of AD is usually difficulty in remembering new information. As the disease progresses, patients may become confused and have problems expressing themselves. Their behavior and personality can also change. In advanced AD, patients need help with daily activities like dressing and eating, and eventually lose their ability to recognize relatives and to communicate. There is no cure for AD but a class of drugs called “cholinesterase inhibitors” can sometimes temporarily slow the worsening of symptoms. Three cholinesterase inhibitors—donepezil, rivastigmine, and galantamine—are currently approved for use in mild-to-moderate AD.
Why Was This Study Done?
Some experts have questioned the efficacy of cholinesterase inhibitors in AD, but other experts and patient support groups have called for these drugs to be given to patients with a condition called mild cognitive impairment (MCI) as well as to those with mild AD. People with MCI have memory problems that are more severe than those normally seen in people of their age but no other symptoms of dementia. They are thought to have an increased risk of developing AD, but it is not known whether everyone with MCI eventually develops AD, and there is no standardized way to diagnose MCI. Despite these uncertainties, several clinical trials have investigated whether cholinesterase inhibitors prevent progression from MCI to AD. In this study, the researchers have assessed whether the results of these trials provide any evidence that cholinesterase inhibitors can prevent MCI progressing to AD.
What Did the Researchers Do and Find?
The researchers conducted a systematic review of the medical literature to find trials that had addressed this issue, which met criteria that they had defined clearly in advance of their search. They identified three published and five unpublished randomized controlled trials (studies in which patients randomly receive the test drug or an inactive placebo) that investigated the effect of cholinesterase inhibitors on the progression of MCI. The researchers obtained the results of six of these trials—four examined the effect of cholinesterase inhibitors on the conversion of MCI to clinically diagnosed AD or dementia (the primary end point); all six examined the effect of the drugs on several secondary end points (for example, individual aspects of cognitive function). None of the drugs produced a statistically significant difference (a difference that is unlikely to have happened by chance) in the probability of progression from MCI to AD. The only statistically significant secondary end point after adjustment for multiple comparisons (when many outcomes are considered, false positive results can occur unless specific mathematical techniques are used to prevent this problem) was a decrease in the rate of brain shrinkage associated with galantamine treatment. More patients treated with cholinesterase inhibitors dropped out of trials because of adverse effects than patients given placebo. Finally, in the one trial that reported all causes of deaths, one participant who received placebo and six who received galantamine died.
What Do These Findings Mean?
These findings suggest that the use of cholinesterase inhibitors is not associated with any delay in the onset of clinically diagnosed AD or dementia in people with MCI. They also show that the use of these drugs has no effect on most surrogate (substitute) indicators of AD but that the risks associated with their use are not negligible. However, because MCI has not yet been clearly defined as a clinical condition that precedes dementia, some (even many) of the patients enrolled into the trials that the researchers assessed may not actually have had MCI. Thus, further clinical trials are needed to clarify whether cholinesterase inhibitors can delay the progression of MCI to dementia, but these additional trials should not be done until the diagnosis of MCI has been standardized.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040338.
An essay by Matthews and colleagues, in the October 2007 issue of PLoS Medicine, discusses how mild cognitive impairment is currently diagnosed
The US Alzheimer's Association provides information about all aspects of Alzheimer disease, including fact sheets on treatments for Alzheimer disease and on mild cognitive impairment
The UK Alzheimer's Society provides information for patients and caregivers on all aspects of dementia, including drug treatments and mild cognitive impairment
The UK charity DIPEx provides short video clips of personal experiences of care givers of people with dementia
doi:10.1371/journal.pmed.0040338
PMCID: PMC2082649  PMID: 18044984
17.  Cholinesterase Inhibitors and Hospitalization for Bradycardia: A Population-Based Study 
PLoS Medicine  2009;6(9):e1000157.
Laura Park-Wyllie and colleagues examined the health records of more than 1.4 million older adults and show that initiation of cholinesterase inhibitor therapy is associated with a more than doubling of the risk of hospitalization for bradycardia.
Background
Cholinesterase inhibitors are commonly used to treat dementia. These drugs enhance the effects of acetylcholine, and reports suggest they may precipitate bradycardia in some patients. We aimed to examine the association between use of cholinesterase inhibitors and hospitalization for bradycardia.
Methods and Findings
We examined the health care records of more than 1.4 million older adults using a case-time-control design, allowing each individual to serve as his or her own control. Case patients were residents of Ontario, Canada, aged 67 y or older hospitalized for bradycardia between January 1, 2003 and March 31, 2008. Control patients (3∶1) were not hospitalized for bradycardia, and were matched to the corresponding case on age, sex, and a disease risk index. All patients had received cholinesterase inhibitor therapy in the 9 mo preceding the index hospitalization. We identified 1,009 community-dwelling older persons hospitalized for bradycardia within 9 mo of using a cholinesterase inhibitor. Of these, 161 cases informed the matched analysis of discordant pairs. Of these, 17 (11%) required a pacemaker during hospitalization, and six (4%) died prior to discharge. After adjusting for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor (adjusted odds ratio [OR] 2.13, 95% confidence interval [CI] 1.29–3.51). The risk was similar among individuals with pre-existing cardiac disease (adjusted OR 2.25, 95% CI 1.18–4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34, 95% CI 1.16–4.71). We found no such association when we replicated the analysis using proton pump inhibitors as a neutral exposure. Despite hospitalization for bradycardia, more than half of the patients (78 of 138 cases [57%]) who survived to discharge subsequently resumed cholinesterase inhibitor therapy.
Conclusions
Among older patients, initiation of cholinesterase inhibitor therapy was associated with a more than doubling of the risk of hospitalization for bradycardia. Resumption of therapy following discharge was common, suggesting that the cardiovascular toxicity of cholinesterase inhibitors is underappreciated by clinicians.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Alzheimer disease and other forms of dementia principally affect people aged over 65. These conditions result in confusion, long term memory loss, irritability, and mood swings. As the population of developed countries ages, the prevalence of dementia is expected to increase significantly. It is forecast that the proportion of people with dementia in the US will quadruple by 2045.
A common treatment for Alzheimer disease is a class of drug called an acetylcholinesterase inhibitor or cholinesterase inhibitor. These include donepezil (brand name Aricept), rivastigmine (marketed as Exelon and Exelon Patch), and galantamine (branded Razadyne).
The benefit of taking cholinesterase inhibitors is generally small and they cannot reverse the effects of dementia. In about 50% of patients they delay the worsening of symptoms for between six months and a year, although a small number of patients may benefit more. They can have unpleasant side effects, which may include diarrhoea and muscle cramps.
Why Was This Study Done?
Existing evidence is inconclusive on whether cholinesterase inhibitors increase the risk of bradycardia, an abnormally slow resting heart rate of below 60 beats a minute, which can cause fatigue, dizziness, fainting, palpitations, shortness of breath, or death. In this paper, the authors use routinely collected health care data to investigate whether an older person taking a cholinesterase inhibitor is at increased risk of bradycardia.
What Did the Researchers Do and Find?
They began by supposing that cholinesterase inhibitors might induce bradycardia soon after a patient first began to take them. To investigate this, they obtained health care data on 1.4 million patients aged 67 or over in Ontario, Canada. They identified 161 patients who had visited a hospital for bradycardia and who had previously taken a cholinesterase inhibitor only within specific periods of time. They found that 139 had taken a cholinesterase inhibitor within the previous three months compared with 22 who had stopped taking it at least six months before.
They compared these cases with up to three “control” patients who matched each of the initial “case” group of 161 patients by age, sex, and risk of bradycardia on the basis of their general health. None of the 466 controls had visited a hospital for bradycardia by the “index date,” that is, the date of hospitalization of the case patient they matched. The researchers found 349 of the control patients had begun to take a cholinesterase inhibitor in the three months prior to the index date, compared with 117 who had stopped taking it at least six months before. A statistical analysis of these data showed that recent initiation of cholinesterase inhibitors was associated with approximately a doubling of the risk of hospitalization for bradycardia.
The authors repeated their procedure to see whether another class of drug, proton pump inhibitors, had a similar effect. As they had expected, it did not. They repeated the analysis for patients taking into account other drugs that slow the heart rate and found that their increased risk of bradycardia when taking a cholinesterase inhibitor persisted. The increase in risk was also similar in patients with pre-existing heart problems.
The researchers' data also showed that, excluding patients who while in the hospital had a pacemaker fitted to control their heart rate, over half of the patients released from hospital started taking a cholinesterase inhibitor again. Of these, a few returned to hospital with bradycardia within 100 days.
What Do These Findings Mean?
Recent guidelines suggest that doctors should not prescribe cholinesterase inhibitors for dementia patients as a matter of course, but weigh the potential risks and benefits. This paper provides evidence of an additional risk, of which at least some doctors are unaware. It was not possible to compare risk for different cholinesterase inhibitors because most patients took donepezil.
A population-based study like this cannot prove that cholinesterase inhibitors cause bradycardia. The authors used routinely collected data and so did not have information on all relevant risk factors, and thus there remains a possibility of bias due to unmeasured factors. In addition the authors had to make assumptions, for instance that patients took the drugs prescribed for them. They also considered only diagnoses of bradycardia made by a hospital doctor and not those made elsewhere, which means the incidence of bradycardia may have been underestimated. A strength of the study is the use of a case-time-control design, which has the advantage of reducing bias due to the different health conditions and lifestyle of individual patients, and also bias due to factors changing over time.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000157.
Wikipedia contains information on Alzheimer disease (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Information on bradycardia and its causes can be found in Wikipedia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The UKs National Health Service provides information on dementia, including symptoms, causes, diagnosis, treatment, and prevention
MedlinePlus provides US-based health information (in English and Spanish)
The US National Institute on Aging provides information on health, relevant to older people, including Alzheimer Disease and dementia (in English and Spanish)
The US Alzheimers Association contains useful information on the disease, including on medication
The Public Health Agency of Canada website provides information on senior health (in English and French)
The UK-based Alzheimers Society provides advice on caring for people with dementia
doi:10.1371/journal.pmed.1000157
PMCID: PMC2742897  PMID: 19787032
18.  Financial Conflicts of Interest and Reporting Bias Regarding the Association between Sugar-Sweetened Beverages and Weight Gain: A Systematic Review of Systematic Reviews 
PLoS Medicine  2013;10(12):e1001578.
Maira Bes-Rastrollo and colleagues examine whether financial conflicts of interest are likely to bias conclusions from systematic reviews that investigate the relationship between sugar-sweetened beverages and weight gain or obesity.
Please see later in the article for the Editors' Summary
Background
Industry sponsors' financial interests might bias the conclusions of scientific research. We examined whether financial industry funding or the disclosure of potential conflicts of interest influenced the results of published systematic reviews (SRs) conducted in the field of sugar-sweetened beverages (SSBs) and weight gain or obesity.
Methods and Findings
We conducted a search of the PubMed, Cochrane Library, and Scopus databases to identify published SRs from the inception of the databases to August 31, 2013, on the association between SSB consumption and weight gain or obesity. SR conclusions were independently classified by two researchers into two groups: those that found a positive association and those that did not. These two reviewers were blinded with respect to the stated source of funding and the disclosure of conflicts of interest.
We identified 17 SRs (with 18 conclusions). In six of the SRs a financial conflict of interest with some food industry was disclosed. Among those reviews without any reported conflict of interest, 83.3% of the conclusions (10/12) were that SSB consumption could be a potential risk factor for weight gain. In contrast, the same percentage of conclusions, 83.3% (5/6), of those SRs disclosing some financial conflict of interest with the food industry were that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain or obesity. Those reviews with conflicts of interest were five times more likely to present a conclusion of no positive association than those without them (relative risk: 5.0, 95% CI: 1.3–19.3).
An important limitation of this study is the impossibility of ruling out the existence of publication bias among those studies not declaring any conflict of interest. However, the best large randomized trials also support a direct association between SSB consumption and weight gain or obesity.
Conclusions
Financial conflicts of interest may bias conclusions from SRs on SSB consumption and weight gain or obesity.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In our daily lives, we frequently rely on the results of scientific research to make decisions about our health. If we are healthy, we may seek out scientific advice about how much exercise to do to reduce our risk of a heart attack, and we may follow dietary advice issued by public health bodies to help us maintain a healthy weight. If we are ill, we expect our treatment to be based on the results of clinical trials and other studies. We assume that the scientific research that underlies our decisions about health-related issues is unbiased and accurate. However, there is increasing evidence that the conclusions of industry-sponsored scientific research are sometimes biased. So, for example, reports of drug trials sponsored by pharmaceutical companies sometimes emphasize the positive results of trials and “hide” unwanted side effects deep within the report or omit them altogether.
Why Was This Study Done?
Although the effects of company sponsors on the conclusions of pharmaceutical research have been extensively examined, little is known about the effects of industry sponsorship on nutrition research, even though large commercial entities are increasingly involved in global food and drink production. It is important to know whether the scientific evidence about nutrition is free of bias because biased information might negatively affect the health of entire populations. Moreover, scientific evidence from nutrition research underlies the formulation of governmental dietary guidelines and food-related public health interventions. In this systematic review, the researchers investigate whether the disclosure of potential financial conflicts of interest (for example, research funding by a beverage company) has influenced the results of systematic reviews undertaken to examine the association between the consumption of highly lucrative sugar-sweetened beverages (SSBs) and weight gain or obesity. Systematic reviews identify all the research on a given topic using predefined criteria. In an ideal world, systematic reviews provide access to all the available evidence on specific exposure–disease associations, but publication bias related to authors' conflicts of interest may affect the reliability of the conclusions of such studies.
What Did the Researchers Do and Find?
The researchers identified 18 conclusions from 17 systematic reviews that had investigated the association between SSB consumption and weight gain or obesity. In six of these reviews, a financial conflict of interest with a food industry was disclosed. Among the reviews that reported having no conflict of interest, 83.3% of the conclusions were that SSB consumption could be a potential risk factor for weight gain. By contrast, the same percentage of reviews in which a potential financial conflict of interest was disclosed concluded that the scientific evidence was insufficient to support a positive association between SSB consumption and weight gain, or reported contradictory results and did not state any definitive conclusion about the association between SSB consumption and weight gain. Reviews in which a potential conflict of interest was disclosed were five times more likely to present a conclusion of no positive association between SSB consumption and weight gain than reviews that reported having no financial conflict of interest.
What Do These Findings Mean?
These findings indicate that systematic reviews that reported financial conflicts of interest or sponsorship from food or drink companies were more likely to reach a conclusion of no positive association between SSB consumption and weight gain than reviews that reported having no conflicts of interest. A major limitation of this study is that it cannot assess which interpretation of the available evidence is truly accurate. For example, the scientists involved in the systematic reviews that reported having no conflict of interest may have had preexisting prejudices that affected their interpretation of their findings. However, the interests of the food industry (increased sales of their products) are very different from those of most researchers (the honest pursuit of knowledge), and recent randomized trials support a positive association between SSB consumption and overweight/obesity. Thus, these findings draw attention to possible inaccuracies in scientific evidence from research funded by the food and drink industry. They do not imply that industry sponsorship of nutrition research should be avoided entirely. Rather, as in other research areas, clear guidelines and principles (for example, sponsors should sign contracts that state that they will not be involved in the interpretation of results) need to be established to avoid dangerous conflicts of interest.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001578.
The Research Ethics Program at the University of California, San Diego provides an overview of conflicts of interest for researchers and details of US regulations and guidelines
The PLOS Medicine series on Big Food examines the activities and influence of the food industry in global health
A PLOS Medicine Research Article by Basu et al. uses mathematical modeling to investigate whether SSB taxation would avert obesity and diabetes in India
A 2012 policy brief from the Yale Rudd Center for Food Policy and Obesity discusses current evidence regarding SSB taxes
The US National Institutes of Health has regulations on financial conflicts of interest for institutions applying to receive funding
Wikipedia has pages on conflict of interest, reporting bias, systematic review, and SSBs (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001578
PMCID: PMC3876974  PMID: 24391479
19.  Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer’s disease 
Brain  2013;136(3):844-858.
The factors driving clinical heterogeneity in Alzheimer’s disease are not well understood. This study assessed the relationship between amyloid deposition, glucose metabolism and clinical phenotype in Alzheimer’s disease, and investigated how these relate to the involvement of functional networks. The study included 17 patients with early-onset Alzheimer’s disease (age at onset <65 years), 12 patients with logopenic variant primary progressive aphasia and 13 patients with posterior cortical atrophy [whole Alzheimer’s disease group: age = 61.5 years (standard deviation 6.5 years), 55% male]. Thirty healthy control subjects [age = 70.8 (3.3) years, 47% male] were also included. Subjects underwent positron emission tomography with 11C-labelled Pittsburgh compound B and 18F-labelled fluorodeoxyglucose. All patients met National Institute on Ageing–Alzheimer’s Association criteria for probable Alzheimer’s disease and showed evidence of amyloid deposition on 11C-labelled Pittsburgh compound B positron emission tomography. We hypothesized that hypometabolism patterns would differ across variants, reflecting involvement of specific functional networks, whereas amyloid patterns would be diffuse and similar across variants. We tested these hypotheses using three complimentary approaches: (i) mass-univariate voxel-wise group comparison of 18F-labelled fluorodeoxyglucose and 11C-labelled Pittsburgh compound B; (ii) generation of covariance maps across all subjects with Alzheimer’s disease from seed regions of interest specifically atrophied in each variant, and comparison of these maps to functional network templates; and (iii) extraction of 11C-labelled Pittsburgh compound B and 18F-labelled fluorodeoxyglucose values from functional network templates. Alzheimer’s disease clinical groups showed syndrome-specific 18F-labelled fluorodeoxyglucose patterns, with greater parieto-occipital involvement in posterior cortical atrophy, and asymmetric involvement of left temporoparietal regions in logopenic variant primary progressive aphasia. In contrast, all Alzheimer’s disease variants showed diffuse patterns of 11C-labelled Pittsburgh compound B binding, with posterior cortical atrophy additionally showing elevated uptake in occipital cortex compared with early-onset Alzheimer’s disease. The seed region of interest covariance analysis revealed distinct 18F-labelled fluorodeoxyglucose correlation patterns that greatly overlapped with the right executive-control network for the early-onset Alzheimer’s disease region of interest, the left language network for the logopenic variant primary progressive aphasia region of interest, and the higher visual network for the posterior cortical atrophy region of interest. In contrast, 11C-labelled Pittsburgh compound B covariance maps for each region of interest were diffuse. Finally, 18F-labelled fluorodeoxyglucose was similarly reduced in all Alzheimer’s disease variants in the dorsal and left ventral default mode network, whereas significant differences were found in the right ventral default mode, right executive-control (both lower in early-onset Alzheimer’s disease and posterior cortical atrophy than logopenic variant primary progressive aphasia) and higher-order visual network (lower in posterior cortical atrophy than in early-onset Alzheimer’s disease and logopenic variant primary progressive aphasia), with a trend towards lower 18F-labelled fluorodeoxyglucose also found in the left language network in logopenic variant primary progressive aphasia. There were no differences in 11C-labelled Pittsburgh compound B binding between syndromes in any of the networks. Our data suggest that Alzheimer’s disease syndromes are associated with degeneration of specific functional networks, and that fibrillar amyloid-β deposition explains at most a small amount of the clinico-anatomic heterogeneity in Alzheimer’s disease.
doi:10.1093/brain/aws327
PMCID: PMC3580269  PMID: 23358601
Alzheimer’s disease; posterior cortical atrophy; logopenic variant of PPA; positron emission tomography (PET); functional networks
20.  Biomarkers for the clinical evaluation of the cognitively impaired elderly: amyloid is not enough 
Imaging in medicine  2012;4(3):343-357.
The number of elderly patients seeking clinical treatment for memory problems will rise sharply in coming years as our population ages. These patients present a challenge for diagnosis and prognosis since cognitive problems in older patients can arise from many etiologies, some of which are curable. With the development of clinically available biomarkers for detecting Alzheimer’s disease pathology in living patients, evaluation of cognitively impaired elderly patients is about to undergo a major paradigm shift. This article describes the two classes of biomarkers available for assessing Alzheimer’s disease risk: those that indicate presence of amyloid pathology and those that provide evidence of neuronal injury and neurodegeneration. We argue that, currently, incorporation of biomarkers of neurodegeneration can help in patient prognosis whereas tests for amyloid, if used in isolation, have potential for harm. Amyloid tests are clinically useful only when evidence suggests progressive cognitive decline or neurodegeneration.
doi:10.2217/iim.12.27
PMCID: PMC3573528  PMID: 23420460
Alzheimer’s disease; amyloid imaging; biomarker; florbetapir; MCI; mild cognitive impairment; MRI; PET
21.  Choroidal Proteins Involved in Cerebrospinal Fluid Production may be Potential Drug Targets for Alzheimer’s Disease Therapy 
Alzheimer’s disease is known to be the most common form of dementia in the elderly. It is clinically characterized by impairment of cognitive functions, as well as changes in personality, behavioral disturbances and an impaired ability to perform activities of daily living. To date, there are no effective ways to cure or reverse the disease. Genetic studies of early-onset familial Alzheimer’s disease cases revealed causative mutations in the genes encoding β-amyloid precursor protein and the γ-secretase-complex components presenilin-1 and presenilin-2, supporting an important role of β-amyloid in the pathogenesis of Alzheimer’s disease. Compromised function of the choroid plexus and defective cerebrospinal fluid production and turnover, with diminished clearance of β-amyloid, may play an important role in late-onset forms of Alzheimer’s disease. If reduced cerebrospinal fluid turnover is a risk factor for Alzheimer’s disease, then therapeutic strategies to improve cerebrospinal fluid flow are reasonable. However, the role of deficient cerebrospinal fluid dynamics in Alzheimer’s disease and the relevance of choroidal proteins as potential therapeutic targets to enhance cerebrospinal fluid turnover have received relatively little research attention. In this paper, we discuss several choroidal proteins, such as Na+-K+ ATPase, carbonic anhydrase, and aquaporin 1, that may be targets for pharmacological up-regulation of cerebrospinal fluid formation. The search for potentially beneficial drugs useful to ameliorate Alzheimer’s disease by facilitating cerebrospinal fluid production and turnover may be an important area for future research. However, the ultimate utility of such modulators in the management of Alzheimer’s disease remains to be determined. Here, we hypothesize that caffeine, the most commonly used psychoactive drug in the world, may be an attractive therapeutic candidate for treatment of Alzheimer’s disease since long-term caffeine consumption may augment cerebrospinal fluid production. Other potential mechanisms of cognitive protection by caffeine have been suggested by recent studies.
doi:10.4137/PMC.S6509
PMCID: PMC3072647  PMID: 21487536
Alzheimer’s disease; aquaporin 1; caffeine; carbonic anhydrase II; cerebrospinal fluid pressure; cerebrospinal fluid production; choroid plexus; intracranial pressure; Na+-K+ ATPase; SLC4A10
22.  Cardiovascular risk factors, cortisol, and amyloid-β deposition in Alzheimer’s Disease Neuroimaging Initiative 
Background
There is epidemiological evidence that cardiovascular risk factors (CVRF) also are risk factors for Alzheimer’s disease, but there is limited information on this from neuro-pathological studies, and even less from in vivo studies. Therefore, we examined the relationship between CVRF and amyloid-β (Aβ) brain burden measured by Pittsburgh Compound B-positron emission tomography (PiB-PET) studies in the Alzheimer’s Disease Neuroimaging Initiative.
Methods
Ninety-nine subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort who had a PiB-PET study measure, apolipoprotein E genotyping data, and information available on CVRF (body mass index [BMI], systolic blood pressure, diastolic blood pressure [DBP1 and cholesterol and fasting glucose test results) were included. Eighty-one subjects also had plasma cortisol C-reactive protein, and superoxide dismutase 1 measurements. Stepwise regression models were used to assess the relation between the CVRF and the composite PiB-PET score.
Results
The first model included the following as baseline variables: age, clinical diagnosis, number of apolipoprotein ε4 alleles, BMI (P = .023), and DBP (P = .012). BMI showed an inverse relation with PiB-PET score, and DBP had a positive relation with PiB-PET score. In the second adjusted model, cortisol plasma levels were also associated with PiB-PET score (P = .004). Systolic blood pressure, cholesterol, or impaired fasting glucose were not found to be associated with PiB-PET values.
Conclusion
In this cross-sectional study, we found an association between Aβ brain burden measured in vivo and DBP and cortisol, indicating a possible link between these CVRF and Aβ burden measured by PiB-PET. These findings highlight the utility of biomarkers to explore potential pathways linking diverse Alzheimer’s disease risk factors.
doi:10.1016/j.jalz.2011.08.008
PMCID: PMC3668456  PMID: 23102118
Alzheimer disease; Vascular risk factors; PiB; Amyloid-β; Cortisol; Blood pressure; Body mass index
23.  Inclusion of Ethical Issues in Dementia Guidelines: A Thematic Text Analysis 
PLoS Medicine  2013;10(8):e1001498.
Background
Clinical practice guidelines (CPGs) aim to improve professionalism in health care. However, current CPG development manuals fail to address how to include ethical issues in a systematic and transparent manner. The objective of this study was to assess the representation of ethical issues in general CPGs on dementia care.
Methods and Findings
To identify national CPGs on dementia care, five databases of guidelines were searched and national psychiatric associations were contacted in August 2011 and in June 2013. A framework for the assessment of the identified CPGs' ethical content was developed on the basis of a prior systematic review of ethical issues in dementia care. Thematic text analysis and a 4-point rating score were employed to assess how ethical issues were addressed in the identified CPGs. Twelve national CPGs were included. Thirty-one ethical issues in dementia care were identified by the prior systematic review. The proportion of these 31 ethical issues that were explicitly addressed by each CPG ranged from 22% to 77%, with a median of 49.5%. National guidelines differed substantially with respect to (a) which ethical issues were represented, (b) whether ethical recommendations were included, (c) whether justifications or citations were provided to support recommendations, and (d) to what extent the ethical issues were explained.
Conclusions
Ethical issues were inconsistently addressed in national dementia guidelines, with some guidelines including most and some including few ethical issues. Guidelines should address ethical issues and how to deal with them to help the medical profession understand how to approach care of patients with dementia, and for patients, their relatives, and the general public, all of whom might seek information and advice in national guidelines. There is a need for further research to specify how detailed ethical issues and their respective recommendations can and should be addressed in dementia guidelines.
Please see later in the article for the Editors' Summary
Editors’ Summary
Background
In the past, doctors tended to rely on their own experience to choose the best treatment for their patients. Faced with a patient with dementia (a brain disorder that affects short-term memory and the ability tocarry out normal daily activities), for example, a doctor would use his/her own experience to help decide whether the patient should remain at home or would be better cared for in a nursing home. Similarly, the doctor might have to decide whether antipsychotic drugs might be necessary to reduce behavioral or psychological symptoms such as restlessness or shouting. However, over the past two decades, numerous evidence-based clinical practice guidelines (CPGs) have been produced by governmental bodies and medical associations that aim to improve standards of clinical competence and professionalism in health care. During the development of each guideline, experts search the medical literature for the current evidence about the diagnosis and treatment of a disease, evaluate the quality of that evidence, and then make recommendations based on the best evidence available.
Why Was This Study Done?
Currently, CPG development manuals do not address how to include ethical issues in CPGs. A health-care professional is ethical if he/she behaves in accordance with the accepted principles of right and wrong that govern the medical profession. More specifically, medical professionalism is based on a set of binding ethical principles—respect for patient autonomy, beneficence, non-malfeasance (the “do no harm” principle), and justice. In particular, CPG development manuals do not address disease-specific ethical issues (DSEIs), clinical ethical situations that are relevant to the management of a specific disease. So, for example, a DSEI that arises in dementia care is the conflict between the ethical principles of non-malfeasance and patient autonomy (freedom-to-move-at-will). Thus, healthcare professionals may have to decide to physically restrain a patient with dementia to prevent the patient doing harm to him- or herself or to someone else. Given the lack of guidance on how to address ethical issues in CPG development manuals, in this thematic text analysis, the researchers assess the representation of ethical issues in CPGs on general dementia care. Thematic text analysis uses a framework for the assessment of qualitative data (information that is word-based rather than number-based) that involves pinpointing, examining, and recording patterns (themes) among the available data.
What Did the Researchers Do and Find?
The researchers identified 12 national CPGs on dementia care by searching guideline databases and by contacting national psychiatric associations. They developed a framework for the assessment of the ethical content in these CPGs based on a previous systematic review of ethical issues in dementia care. Of the 31 DSEIs included by the researchers in their analysis, the proportion that were explicitly addressed by each CPG ranged from 22% (Switzerland) to 77% (USA); on average the CPGs explicitly addressed half of the DSEIs. Four DSEIs—adequate consideration of advanced directives in decision making, usage of GPS and other monitoring techniques, covert medication, and dealing with suicidal thinking—were not addressed in at least 11 of the CPGs. The inclusion of recommendations on how to deal with DSEIs ranged from 10% of DSEIs covered in the Swiss CPG to 71% covered in the US CPG. Overall, national guidelines differed substantially with respect to which ethical issues were included, whether ethical recommendations were included, whether justifications or citations were provided to support recommendations, and to what extent the ethical issues were clearly explained.
What Do These Findings Mean?
These findings show that national CPGs on dementia care already address clinical ethical issues but that the extent to which the spectrum of DSEIs is considered varies widely within and between CPGs. They also indicate that recommendations on how to deal with DSEIs often lack the evidence that health-care professionals use to justify their clinical decisions. The researchers suggest that this situation can and should be improved, although more research is needed to determine how ethical issues and recommendations should be addressed in dementia guidelines. A more systematic and transparent inclusion of DSEIs in CPGs for dementia (and for other conditions) would further support the concept of medical professionalism as a core element of CPGs, note the researchers, but is also important for patients and their relatives who might turn to national CPGs for information and guidance at a stressful time of life.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001498.
Wikipedia contains a page on clinical practice guidelines (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US National Guideline Clearinghouse provides information on national guidelines, including CPGs for dementia
The Guidelines International Network promotes the systematic development and application of clinical practice guidelines
The American Medical Association provides information about medical ethics; the British Medical Association provides information on all aspects of ethics and includes an essential tool kit that introduces common ethical problems and practical ways to deal with them
The UK National Health Service Choices website provides information about dementia, including a personal story about dealing with dementia
MedlinePlus provides links to additional resources about dementia and about Alzheimers disease, a specific type of dementia (in English and Spanish)
The UK Nuffield Council on Bioethics provides the report Dementia: ethical issues and additional information on the public consultation on ethical issues in dementia care
doi:10.1371/journal.pmed.1001498
PMCID: PMC3742442  PMID: 23966839
24.  Accumulation of neutral lipids in peripheral blood mononuclear cells as a distinctive trait of Alzheimer patients and asymptomatic subjects at risk of disease 
BMC Medicine  2009;7:66.
Background
Alzheimer's disease is the most common progressive neurodegenerative disease. In recent years, numerous progresses in the discovery of novel Alzheimer's disease molecular biomarkers in brain as well as in biological fluids have been made. Among them, those involving lipid metabolism are emerging as potential candidates. In particular, an accumulation of neutral lipids was recently found by us in skin fibroblasts from Alzheimer's disease patients. Therefore, with the aim to assess whether peripheral alterations in cholesterol homeostasis might be relevant in Alzheimer's disease development and progression, in the present study we analyzed lipid metabolism in plasma and peripheral blood mononuclear cells from Alzheimer's disease patients and from their first-degree relatives.
Methods
Blood samples were obtained from 93 patients with probable Alzheimer's disease and from 91 of their first-degree relatives. As controls we utilized 57, cognitively normal, over-65 year-old volunteers and 113 blood donors aged 21-66 years, respectively. Data are reported as mean ± standard error. Statistical calculations were performed using the statistical analysis software Origin 8.0 version. Data analysis was done using the Student t-test and the Pearson test.
Results
Data reported here show high neutral lipid levels and increased ACAT-1 protein in about 85% of peripheral blood mononuclear cells freshly isolated (ex vivo) from patients with probable sporadic Alzheimer's disease compared to about 7% of cognitively normal age-matched controls. A significant reduction in high density lipoprotein-cholesterol levels in plasma from Alzheimer's disease blood samples was also observed. Additionally, correlation analyses reveal a negative correlation between high density lipoprotein-cholesterol and cognitive capacity, as determined by Mini Mental State Examination, as well as between high density lipoprotein-cholesterol and neutral lipid accumulation. We observed great variability in the neutral lipid-peripheral blood mononuclear cells data and in plasma lipid analysis of the subjects enrolled as Alzheimer's disease-first-degree relatives. However, about 30% of them tend to display a peripheral metabolic cholesterol pattern similar to that exhibited by Alzheimer's disease patients.
Conclusion
We suggest that neutral lipid-peripheral blood mononuclear cells and plasma high density lipoprotein-cholesterol determinations might be of interest to outline a distinctive metabolic profile applying to both Alzheimer's disease patients and asymptomatic subjects at higher risk of disease.
doi:10.1186/1741-7015-7-66
PMCID: PMC2777188  PMID: 19883495
25.  Transnational Tobacco Company Interests in Smokeless Tobacco in Europe: Analysis of Internal Industry Documents and Contemporary Industry Materials 
PLoS Medicine  2013;10(9):e1001506.
In light lobbying by transnational tobacco companies to remove the European Union ban on the sale of snus (a smokeless tobacco product), Silvy Peeters and Anna Gilmore explore the motivation behind tobacco companies' interests in smokeless tobacco products in Europe.
Please see later in the article for the Editors' Summary
Background
European Union (EU) legislation bans the sale of snus, a smokeless tobacco (SLT) which is considerably less harmful than smoking, in all EU countries other than Sweden. To inform the current review of this legislation, this paper aims to explore transnational tobacco company (TTC) interests in SLT and pure nicotine in Europe from the 1970s to the present, comparing them with TTCs' public claims of support for harm reduction.
Methods and Results
Internal tobacco industry documents (in total 416 documents dating from 1971 to 2009), obtained via searching the online Legacy Tobacco Documents Library, were analysed using a hermeneutic approach. This library comprises documents obtained via litigation in the US and does not include documents from Imperial Tobacco, Japan Tobacco International, or Swedish Match. To help overcome this limitation and provide more recent data, we triangulated our documentary findings with contemporary documentation including TTC investor presentations. The analysis demonstrates that British American Tobacco explored SLT opportunities in Europe from 1971 driven by regulatory threats and health concerns, both likely to impact cigarette sales negatively, and the potential to create a new form of tobacco use among those no longer interested in taking up smoking. Young people were a key target. TTCs did not, however, make SLT investments until 2002, a time when EU cigarette volumes started declining, smoke-free legislation was being introduced, and public health became interested in harm reduction. All TTCs have now invested in snus (and recently in pure nicotine), yet both early and recent snus test markets appear to have failed, and little evidence was found in TTCs' corporate materials that snus is central to their business strategy.
Conclusions
There is clear evidence that BAT's early interest in introducing SLT in Europe was based on the potential for creating an alternative form of tobacco use in light of declining cigarette sales and social restrictions on smoking, with young people a key target. We conclude that by investing in snus, and recently nicotine, TTCs have eliminated competition between cigarettes and lower-risk products, thus helping maintain the current market balance in favour of (highly profitable) cigarettes while ensuring TTCs' long-term future should cigarette sales decline further and profit margins be eroded.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about 5 million people die from cancer, heart disease, and other tobacco-related diseases. In recent years, to reduce this growing loss of life, international and national bodies have drawn up various tobacco control conventions and directives. For example, the European Union (EU) Directives on tobacco control call for member states to ban tobacco advertising, promotion, and sponsorship and to adopt taxation policies aimed at reducing tobacco consumption. The 2001 EU Tobacco Products Directive also bans the sale of snus, a form of smokeless tobacco (SLT), in all EU countries except Sweden. Snus, which originated in Sweden in the early 19th century, is a moist tobacco product that is placed under the upper lip. Although snus is considerably less harmful than smoking, the sale of snus was banned in the EU in 1992 because of fears that it might cause cancer and was being marketed to young people. When Sweden joined the EU in 1994, exemption from the ban was made a condition of the membership treaty.
Why Was This Study Done?
Transnational tobacco companies (TTCs) have been investing in European snus manufacturers since 2002 and more recently in pure nicotine products, and it has been suggested that, faced with declining cigarette markets in Europe and elsewhere, TTCs are preparing for a “post-cigarette era”. Since 2008, TTCs have been lobbying EU member states and the European Commission to remove the ban on snus sales, arguing that public health would be improved if governments allowed potentially reduced-harm products like snus onto the market. At the end of 2012, however, the European Commission proposed that the ban on snus sales should be continued. Here, to help inform this controversial policy debate, the researchers explore the interest of TTCs in SLT and pure nicotine in Europe from the 1970s to the present by examining internal tobacco documents and compare these interests with public claims of support for harm reduction made by TTCs.
What Did the Researchers Do and Find?
By searching the Legacy Tobacco Documents Library (internal tobacco industry documents released following US litigation cases), the researchers identified 416 documents that detail the historical interest of TTCs in SLT and pure nicotine and their efforts to enter European markets, and to influence national and EU public-health policy. The researchers analyzed these documents using a “hermeneutic” approach—methodical reading and re-reading of the documents to identify themes and sub-themes. Finally, they used TTC investor presentations and other documents to confirm these themes and to provide recent data on TTC investment in SLT. British American Tobacco (BAT) explored the opportunities for marketing SLT products in Europe from 1971 onwards. This exploration was driven by regulatory threats and health concerns, both of which were likely to impact tobacco sales, and by the potential to create a new form of tobacco use among people no longer interested in taking up smoking. TTCs did not begin to invest in SLT, however, until 2002, a time when EU cigarette sale volumes started to decline, smoke-free legislation was being introduced, and tobacco harm reduction first became a major public-health issue. All the TTCs have now invested in snus even though snus test markets appear to have failed and even though there is little evidence in corporate materials that snus is central to the business strategy of TTCs.
What Do These Findings Mean?
These findings suggest that BAT's early interest in SLT in Europe was driven by business concerns and was based on the potential for creating an alternative form of tobacco use among people—particularly young people—who would no longer take up smoking because of health concerns. They also suggest that TTC investments in snus were defensive—by buying up snus manufacturers and more recently nicotine producers, TTCs have eliminated competition between cigarettes and lower-risk products, thereby helping to maintain the current market balance in favor of cigarettes while ensuring the long-term future of TTCs should cigarette sales decline further. Although these findings are limited by the possibility that some relevant documents may have been omitted from this analysis, they nevertheless raise the concern that, if TTC investment in SLT continues, competition between cigarettes and SLT will reduce the potential for harm reduction to benefit public health. Legalization of snus sales in the European Union may therefore have considerably less benefit than envisaged.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001506.
The World Health Organization provides information about the dangers of tobacco (in several languages) and about the Framework Convention on Tobacco Control, an international treaty for tobacco control; for information about the tobacco industry's influence on policy, see the 2009 World Health Organization report Tobacco interference with tobacco control
Details of European Union legislation on the manufacture, presentation, and sale of tobacco products is available (in several languages)
Wikipedia has pages on tobacco harm reduction and on snus (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The Legacy Tobacco Documents Library is a searchable public database of tobacco company internal documents detailing their advertising, manufacturing, marketing, sales, and scientific activities
The UK Centre for Tobacco Control Studies is a network of UK universities that undertakes original research, policy development, advocacy, and teaching and training in the field of tobacco control
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
TobaccoTactics.org, an online resource managed by the University of Bath, provides up-to-date information on the tobacco industry and their tactics to influence tobacco regulation
doi:10.1371/journal.pmed.1001506
PMCID: PMC3769209  PMID: 24058299

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