BRCA1 Methylation Tied to Ovarian Cancer Risk

DNA repair gene may be nonfunctional despite ‘normal’ test result

BRCA1 mutations are well-known to predispose to ovarian cancer risk. But now a new study, appearing in the Annals of Internal Medicine, suggests that methylation of normal BRCA1 genes might be a major ovarian cancer risk factor. In this 150-Second Analysis, F. Perry Wilson, MD, MSCE investigates the data.

Testing for BRCA mutations in women with a compelling family history of breast or ovarian cancer has become relatively commonplace. The sequela of a positive test can be life-changing, with many women opting for prophylactic mastectomy and oophorectomy.

But what if the genetic test is normal? Well, according to a new paper appearing in the Annals of Internal Medicine, a “normal” BRCA test may not mean the gene is functioning properly.

BRCA1 is a DNA-repair protein. When it is inactivated by mutation, errors in DNA can build up over time, and eventually we see cancers develop – typically breast and ovarian cancers.

But there’s more than one way to inactivate a gene. Remember that a gene is transcribed when its promoter region is accessible to the transcription machinery.

The promoter can be blocked by methylation, preventing transcription.

And an untranscribed BRCA1 might as well be mutant – it can’t repair DNA if it isn’t there.

The study of interest examined 1,541 women with ovarian cancer and no BRCAmutations. They matched these cases with 3,682 controls. Most of the women in both groups had normal BRCA1, but roughly 9% of those with cancer had abnormal methylation in the BRCA1 promoter – compared to only around 4% of control participants. After adjustment for other factors, having methylated BRCA1conferred almost a threefold higher risk of ovarian cancer.

These findings, which were replicated across two cohorts, make abnormal BRCA1 methylation the second strongest risk factor for ovarian cancer beyond an out-and-out BRCA1 mutation.

One thing I want to point out here – these methylation results did not come from breast tissue – these were the results in white blood cells. It’s already pretty clearthat abnormal methylation at the tissue level can promote cancer in that tissue – this is one of the best studies yet to demonstrate that the methylation problem may be global.

But how does this abnormal methylation happen? Is it some environmental exposure that we could potentially avoid? The researchers believe the relevant exposure happens in utero or early in life, based on data from a cohort of newborns.

What that exposure is, though, remains in the mists of science’s undiscovered country.

Aside from identifying a new risk factor for ovarian cancer, there is something more compelling about this study. Because the BRCA1 gene in these women is normal, one can imagine a therapy that would reduce methylation allowing the gene to be properly transcribed. Would this open the door to a novel treatment in a subset of women with ovarian cancer? Or perhaps a therapy that would help prevent ovarian cancer in the first place? I’m sure that’s something we would all promote.

Butter Is Back.

Julia Child, goddess of fat, is beaming somewhere. Butter is back, and when you’re looking for a few chunks of pork for a stew, you can resume searching for the best pieces — the ones with the most fat. Eventually, your friends will stop glaring at you as if you’re trying to kill them.

That the worm is turning became increasingly evident a couple of weeks ago, when a meta-analysis published in the journal Annals of Internal Medicine found that there’s just no evidence to support the notion that saturated fat increases the risk of heart disease. (In fact, there’s some evidence that a lack of saturated fat may be damaging.) The researchers looked at 72 different studies and, as usual, said more work — including more clinical studies — is needed. For sure. But the days of skinless chicken breasts and tubs of I Can’t Believe It’s Not Butter may finally be drawing to a close.

The tip of this iceberg has been visible for years, and we’re finally beginning to see the base. Of course, no study is perfect and few are definitive. But the real villains in our diet — sugar and ultra-processed foods — are becoming increasingly apparent. You can go back to eating butter, if you haven’t already.

This doesn’t mean you abandon fruit for beef and cheese; you just abandon fake food for real food, and in that category of real food you can include good meat and dairy. I would argue, however, that you might not include most industrially produced animal products; stand by.

Since the 1970s almost everyone in this country has been subjected to a barrage of propaganda about saturated fat. It was bad for you; it would kill you. Never mind that much of the nonsaturated fat was in the form of trans fats, now demonstrated to be harmful. Never mind that many polyunsaturated fats are chemically extracted oils that may also, in the long run, be shown to be problematic.

Never mind, too, that the industry’s idea of “low fat” became the emblematic SnackWell’s and other highly processed “low-fat” carbs (a substitution that is probably the single most important factor in our overweight/obesity problem), as well as reduced fat and even fat-free dairy, on which it made billions of dollars. (How you could produce fat-free “sour cream” is something worth contemplating.)

But let’s not cry over the chicharrones or even nicely buttered toast we passed up. And let’s not think about the literally millions of people who are repelled by fat, not because it doesn’t taste good (any chef will tell you that “fat is flavor”) but because they have been brainwashed.

Rather, let’s try once again to pause and think for a moment about how it makes sense for us to eat, and in whose interest it is for us to eat hyperprocessed junk. The most efficient summary might be to say “eat real food” and “avoid anything that didn’t exist 100 years ago.” You might consider a dried apricot (one ingredient) versus a Fruit Roll-Up (13 ingredients, numbers 2, 3 and 4 of which are sugar or forms of added sugar). Or you might reflect that real yogurt has two or three ingredients (milk plus bacteria, with some jam or honey if you like) and that the number in Breyers YoCrunch Cookies n’ Cream Yogurt is unknowable (there are a few instances of “and/or”) but certainly at least 18.

Many things have gone awry with the way we produce food. And it isn’t just the existence of junk food but the transformation of ingredients we could once take for granted or thought of as “healthy.” Indeed, meat, dairy, wheat and corn have become foods that frequently contain antibiotics and largely untested chemicals, or are produced using hybrids or methods that have increased yield but may have produced unwanted results.

Vitamin pills are a waste of money, offer no health benefits and could be harmful – study

Evidence from the study suggested that ‘supplementing the diet of well-nourished adults…has no clear benefit and might even be harmful’

Vitamin pills are a waste of money, usually offer no health benefits and could even be harmful, a group of leading scientists has said.

A study of nearly 500,000 people, carried out by academics from the University of Warwick and the Johns Hopkins School of Medicine in Baltimore, USA, has delivered a damning verdict on the claims made by the vitamin supplement industry.

Evidence from the study suggested that “supplementing the diet of well-nourished adults…has no clear benefit and might even be harmful”, despite one in three Britons taking vitamins or mineral pills.

According to The Times, scientists involved in the study, which was published in the Annals of Internal Medicine, concluded that companies selling supplements were fuelling false health anxieties to offer unnecessary cures. The industry in the UK is thought to be worth more than £650 million annually.

Researchers declared ‘case closed’ on the vitamin and mineral pills after making their conclusion based on the study of half-a-million people along with three separate research papers.

Evidence from the study suggested that

Evidence from the study suggested that “supplementing the diet of well-nourished adults…has no clear benefit and might even be harmful”, despite one in three Britons taking vitamins or mineral pills.

One of the research papers involved the retrospective study of 24 previous trials. In total 450,000 people were involved in the trials and the paper concluded that there was no beneficial effect on mortality from taking vitamins.

Another examined 6,000 elderly men and found no improvement on cognitive decline after 12 years of taking supplements, while a third saw no advantage of supplements among 1,700 men and women with heart problems over an average study of five years.

The experts said most supplements should be avoided as their use is not justified, writing: “These vitamins should not be used for chronic disease prevention. Enough is enough.”

The scientists argued that the average Western diet is sufficient to provide the necessary vitamins the body needs.

Edgar Miller, of the Johns Hopkins School of Medicine, said: “There are some that advocate we have many nutritional deficiencies in our diet. The truth is though we are in general overfed, our diet is completely adequate.”

He added: “These companies are marketing products to us based on perceptions of deficiencies. They make us think our diet is unhealthy, and that they can help us make up for these deficiencies and stop chronic illnesses.

“The group that needs these is very small. It’s not the general population.”

Dr Miller continued: “There’s something for everything: preventing joint pains, stopping heart disease. If you’re going to spend your money on something every month, is this really the best option?”

The NHS advised recently that other than women taking folic acid to help them conceive and the elderly and children under five benefiting from vitamin D, supplementary vitamins would be surplus to that already gained through diet, The Times said.

The Health Food Manufacturers’ Association said vitamin supplements provided people with “nutritional insurance”.

In July 2011 the Advertising Standards Agency criticised Vitabiotics Ltd for an advert headlined: ‘Advanced Nutrients For The Brain’.

They ruled that the implied claims that “recent research had shown that B vitamins could help maintain brain function and performance’ were not substantiated and were “misleading”.

Government Experts Say Supplements Don’t Prevent Heart Disease, Cancer.

Americans spend nearly $12 billion each year on vitamin supplements, hoping they will steer us away from diseases like cancer and heart attacks. But it turns out they’re just a drain on our wallets.

Should healthy people take supplements to keep them healthy? A panel of experts convened by the government, the U.S. Preventive Services Task Force, says that for most vitamins and minerals, there is not enough evidence to determine whether the pills can lower risk of heart disease or cancer. And when it comes to beta-carotene (found in carrots and tomatoes) and vitamin E, there is no evidence that they can protect against either heart disease or cancer; in fact, beta-carotene use contributed to an increased risk of lung cancer in smokers.

That will come as a surprise to most Americans, who pop pills of omega-3 fatty acids hoping to fend off a heart attack or down vitamins C and E, which are high in antioxidants, to counteract the free-radical damage that contributes to cancer. “In the absence of clear evidence about the impact of most vitamins and multivitamins on cardiovascular disease and cancer, health care professionals should counsel their patients to eat a healthy, well-balanced diet that is rich in nutrients. They should also continue to consider the latest scientific research, their own experiences, and their patient’s health history and preferences when having conversations about nutritional supplements,” task-force member Dr. Wanda Nicholson said in a statement.

(MORE: Vitamin D and Calcium Supplements May Not Prevent Fractures)

The panel based its conclusion on a review of 26 studies, conducted from 2005 to ’13, some of which involved single supplements and others that investigated multivitamins and their relationship to heart disease, cancer and death outcomes. The review built on the panel’s previous report on supplements, in 2003, in which the task-force members said that there was not enough evidence to recommend vitamin A, C or E supplements, multivitamins or antioxidant combinations to prevent heart disease or cancer. At that time, the members also recommended against beta-carotene supplements because of their connection to a higher risk of lung cancer among smokers. In the current review, the members considered additional data on other vitamins and nutrients, including vitamins B and D, as well as zinc, iron, magnesium, niacin and calcium.

The conclusions apply to otherwise healthy people who take the supplements to prevent disease, so it’s not clear how effective, if at all, the pills can be in those at higher risk of heart problems or cancer. There have been hints, however, that the pills might not be the panacea that many people hoped they would be. In 2012, for example, a study published in the Journal of the American Medical Association showed that omega-3 supplements, touted as a powerful weapon against heart disease, did not lower risks of heart attack, stroke, or death from heart disease or any cause. Another study published in 2011 even linked vitamin-and-supplement consumption to a higher risk of death, reporting that women who took multivitamins were 6% more likely to die over a 19-year period, compared with women not taking them.

(MORE: Hold the Salmon: Omega-3 Fatty Acids Linked to Higher Risk of Cancer)

Why the takedown of vitamins, especially if they are so prevalent in good-for-you foods such as fruits and vegetables? Experts believe that the benefits of nutrients like vitamins may depend on how they are presented to the body; some may need the help of other compounds found in their natural form that are inadvertently stripped from individual pills that try to concentrate the health benefits of specific vitamins or minerals. “[T]he physiologic systems affected by vitamins and other antioxidant supplements are so complex that the effects of supplementing with only 1 or 2 components is generally ineffective or actually does harm,” write the authors in their report, published in the Annals of Internal Medicine.

They recognize, however, that their conclusions are based on relatively few studies, since few trials have addressed the question of whether supplements can prevent disease in healthy people. So the results hold only until more data become available to understand the association more completely. In the meantime, the best way to take advantage of any health-promoting effects of nutrients like vitamins and minerals is to get them in their natural state, by eating a well-balanced diet high in low-fat dairy, fruits, vegetables and lean proteins.

Home Test for Pharyngitis May Reduce Unneeded Strep Cultures.

A patient-driven approach to streptococcal pharyngitis diagnosis using a new home test score might save on unnecessary physician visits, cultures, and treatment, according to a retrospective cohort study published online November 4 in the Annals of Internal Medicine. However, some experts are skeptical of the home score algorithm and of its potential cost-savings.

“Globally, group A streptococcal (GAS) pharyngitis affects hundreds of millions of persons each year,” write Andrew M. Fine, MD, MPH, from the Division of Emergency Medicine-Main 1, Boston Children’s Hospital in Massachusetts, and colleagues. “In the United States, more than 12 million persons make outpatient visits for pharyngitis; however, clinicians cannot differentiate GAS pharyngitis from other causes of acute pharyngitis (for example, viral) on the basis of a physical examination of the oropharynx.”

Most cases of sore throat are viral, rather than bacterial, and therefore are self-limiting and transient even without antibiotic treatment. To classify risk for GAS pharyngitis and guide management of adults with acute pharyngitis, the American College of Physicians and Centers for Disease Control and Prevention recommend use of clinical scores to identify low-risk patients. According to consensus guidelines, such patients should not be tested or treated for GAS pharyngitis.

The goal of this study was to help patients decide when to visit a clinician for evaluation of sore throat. The study sample consisted of 71,776 patients at least 15 years of age who were evaluated for pharyngitis from September 2006 to December 2008 at one of a national chain of retail health clinics.

Using information from patient-reported clinical variables, as well as local incidence of GAS pharyngitis, the investigators created a score and compared it with the Centor score and other traditional scores, using information from clinicians’ assessments. Clinical variables in the new score were fever, absence of cough, and age.

The investigators estimated outcomes if patients who were at least 15 years of age with sore throat did not visit a clinician when the new score indicated less than 10% likelihood of GAS pharyngitis, compared with being managed by clinicians following guidelines using the Centor score. The researchers suggest that following this strategy would avoid 230,000 clinician visits in the United States each year, and that 8500 patients with GAS pharyngitis who would have received antibiotics under clinician management would not receive antibiotics.

A limitation of this approach is current lack of availability of real-time information about the local incidence of GAS pharyngitis, which is needed to calculate the new score. Study limitations include retrospective design and reliance on self-report of symptoms.

“A patient-driven approach to pharyngitis diagnosis that uses this new score could save hundreds of thousands of visits annually by identifying patients at home who are unlikely to require testing or treatment,” the authors write.

Experts Question Limitations and Cost-Savings of the New Score

In an accompanying editorial, Edward L. Kaplan, MD, MMC, from the Department of Pediatrics, University of Minnesota Medical School in Minneapolis, warns of limitations of the new home score. These include overly broad age range, as GAS pharyngitis is rare in persons older than 50 years, and the assumption that GAS pharyngitis has even prevalence across communities.

Dr. Kaplan recommends stratification by age categories and notes that uncomplicated GAS pharyngitis has not been reportable to health departments for several decades in most states, making incidence difficult to determine. Other limitations include failure to account for potential effects of the decisions made by the multiple clinicians from more than 70 clinics attended by patients in this sample, and lack of differentiation of true GAS infection from upper respiratory tract “carriers” among adults.

“Until we have a proven cost-effective vaccine to protect against Streptococcus pyogenes, we cannot expect the magnitude of this medical and public health issue to decrease,” Dr. Kaplan writes. “Even if a cost-effective vaccine is developed, how it may affect true infections and the carrier state in children may be entirely different in adults. Fine and colleagues have proposed an interim approach, but there are surely others.”

In a second editorial, Robert M. Centor, MD, from the University of Alabama at Birmingham in Huntsville, questions the potential cost-savings if the new score were widely used. Alternative strategies to improve treatment and reduce costs include clinical assessment that eliminates testing for patients at low risk, as well as the use of generic antibiotics for those with GAS pharyngitis. He also warns that all guidelines and recommendations for GAS pharyngitis apply only to patients who have had symptoms for fewer than 3 days.

“If symptoms persist or worsen, then the patient no longer has acute pharyngitis; therefore, we should use a different diagnostic and therapeutic approach,” he writes.

Other questions posed by Dr. Centor include whether patients would actually download and use such a test before deciding whether to seek medical care for sore throat and why many physicians, clinics, and emergency departments do not follow published guidelines recommending against antibiotic use for patients with low probability of GAS pharyngitis.

“Although the goals [of this study] are admirable, the approach does not seem practical or cost-saving,” Dr. Centor concludes. “We have more practical strategies for decreasing costs for patients with sore throat.

Healthy Diet, Healthy Aging.

Middle-aged women following a healthy Mediterranean-type diet — with an emphasis on fruits, vegetables, whole grains and fish, moderate amounts of alcohol, and little red meat — have much greater odds of healthy aging later on, a new study reports.

“In this study, women with healthier dietary patterns at midlife were 40% more likely to survive to age 70 or over free of major chronic diseases and with no impairment in physical function, cognition or mental health,” said lead study author, Cécilia Samieri, PhD, Institut pour la Santé Publique et le Developpement, Université Bordeaux, France.

This new study adds to growing research on the health benefits of the Mediterranean diet recently reported. Various studies have shown that this diet may contribute to reduced fasting glucose concentrations and lipid levels in those at risk for diabetes, may lower the risk for cardiovascular events and stroke, and improve cognition.

The new study was published in the November 5 issue of Annals of Internal Medicine.

The analysis included 10,670 participants in the Nurses’ Health Study, which began in 1976 when female nurses aged 30 to 55 years completed a mail-in survey. Since then, study participants have been closely followed on a regular basis.

In 1980, participants completed a food-frequency questionnaire (FFQ) that asked how often on average they consumed standard portions of various foods. This questionnaire was repeated in 1984 and 1986 and then every 4 years.

To assess dietary quality at midlife, researchers averaged information from the 1984 and 1986 FFQs. They calculated scores on 2 diet indexes:

  • Alternative Healthy Eating Index-2010 (AHEI-2010): This index considers greater intake of vegetables, fruits, whole grains, nuts, legumes, and polyunsaturated fatty acids (PUFAs); lower intake of sugar-sweetened beverages, red or processed meats, trans fats, and sodium; and moderate intake of alcoholic beverages. Total AHEI-2010 scores range from 0 (nonadherence) to 110 (perfect adherence).

  • Alternate Mediterranean diet (A-MeDi): Developed to assess adherence to the traditional Mediterranean diet, this index includes 9 components that are similar to those in the AHEI-2010. Total A-MeDi scores range from 0 (nonadherence) to 9 (perfect adherence).

In 1992, 1996, and 2000, participants completed the Medical Outcomes Short-Form 36 Health Survey, a questionnaire that evaluates 8 health concepts, including mental health and physical functioning. Scores from the Telephone Interview for Cognitive Status, an adaptation of the Mini-Mental State Examination, were used to evaluate cognitive health. From 1995 to 2001, a cognitive study was administered to participants aged 70 years or older.

Investigators separated “healthy” from “usual” aging on the basis of 4 health domains. Overall, 11.0% of the participants were considered healthy (and so were free of chronic diseases, such as cancers, myocardial infarction, and diabetes, and with no limitation in cognitive function, mental health, and physical function), and the remaining participants were considered usual agers.

Several health domains were typically impaired among the “usual” agers, said Dr. Samieri. “For example, 33% had both chronic diseases and limitations in cognitive, physical, or mental health; 64% had only limitations in cognitive, physical, or mental health; and 3.4% had only 1 or more chronic diseases.”

The analysis revealed that greater adherence at midlife to AHEI-2010 and A-MeDi was strongly associated with greater odds of healthy aging (P for trend < .001 for AHEI-2010; P for trend = .002 for A-Medi).

For example, compared with women in the worst quintile of diet scores, women in the highest quintile of the AHEI-2010 and A-MeDi scores had 34% (95% confidence interval [CI], 9% – 66%) and 46% (95% CI, 17% – 83%) greater odds of healthy aging, respectively.

Individual Components

When they analyzed individual dietary components, researchers found statistically significant associations of greater intake of fruits (odds ratio [OR] for upper versus lower quintiles, 1.46) and alcohol (OR, 1.28), and lower intakes of sweetened beverages (OR, 1.28) and PUFAs (OR, 1.38) with healthy aging (P for trend ≤ .04).

The authors noted that they could not exclude participants with impaired cognition, mental health, and physical function in midlife, and although probably few women had severe impairments at baseline, reverse causation in these participants may still be possible. Because they didn’t follow participants through to death or onset of a condition that would classify them as no longer healthy, researchers couldn’t prospectively estimate risks for transitioning from healthy to usual aging. As well, measurement errors may have occurred in the assessment of dietary patterns.

Other possible limitations were that the study was observational and, because it included mostly white women, its results may not be generalizable to other populations.

Middle age is probably the most relevant period of exposure for preventing chronic conditions of aging that develop over many years.

“It’s largely accepted that cumulative exposures to environmental risk factors over the lifespan are probably more important than late-life exposures to determine health in older ages,” said Dr. Samieri. “Several mechanisms of age-related chronic diseases, for example, atherosclerosis in cardiac diseases, brain lesions in dementia, start in midlife.”

Various researchers have reported on other newly documented health benefits of the Mediterranean diet, including the following:

Evidence Insufficient for Routine Dementia Screening.

There is still not enough clear evidence to recommend routine screening for dementia, a draft recommendation  posted today by the US Preventive Services Task Force (USPSTF) concludes.

The new recommendation was based on a systematic review of literature on the topic published online October 22 in the Annals of Internal Medicine, reported by Medscape Medical News at that time.

But while the overall evidence on routine screening is insufficient, clinicians should remain alert to early signs or symptoms of cognitive impairment and evaluate accordingly, the USPSTF said in a statement.

The draft recommendation applies to adults over age 65 years without signs or symptoms of cognitive impairment. It will be posted on the USPSTF Web site and be open for public comment before the Task Force develops a final recommendation.

This recommendation updates the 2003 USPSTF statement that also concluded that the evidence was insufficient to recommend for or against routine screening for dementia. Unlike that earlier recommendation, this updated version considered the evidence on screening for and treatment of mild cognitive impairment in addition to dementia, and on how screening affects decision-making and planning.

Brief Screening Tools

With new data on screening accuracy, the Task Force was able to conclude that there is adequate information on the accuracy of some brief screening tools to identify dementia. The most widely studied instrument is the Mini-Mental State Examination. For the most commonly reported cut points (23/24 or 24/25), the pooled sensitivity from 14 studies was 88.3% (95% confidence interval [CI], 81.3% – 92.9%) and specificity was 86.2% (95% CI, 81.8% – 89.7%).

Other screening tools include the Clock Draw Test, Mini-Cog, Memory Impairment Screen, Abbreviated Mental Test, Short Portable Mental Status Questionnaire, Free and Cued Selective Reminding Test, 7-Minute Screen, Telephone Interview for Cognitive Status, and Informant Questionnaire on Cognitive Decline in the Elderly. These tests have reasonable test performance according to some studies, but their sensitivity or specificity ranged widely and optimal diagnostic cut-points for many are unclear, the statement said.

The new data suggest that treatment of mild to moderate dementia with acetylcholinesterase inhibitors (AChEIs) and memantine, and with nonpharmacologic interventions, such as cognitive stimulation and exercise, results in small improvement in cognitive function, and that interventions aimed at caregivers result in reduced caregiver burden and depression. However, the clinical significance of these improvements is uncertain, according to the Task Force report.

No published evidence was found on the effect of screening on decision-making or planning by patients, clinicians, or caregivers, the Task Force concluded.

Critical Gap

“This is a critical gap in the evidence, and more research is needed so we can better understand the benefits and risks of screening and understand the impact early detection can have on the lives of patients and their families,” commented Task Force member Douglas K. Owens, MD, in press materials accompanying the draft document.

More data will be required before such screening could be recommended. “If we had information on treatments that might be available in early dementia that were highly effective, I think that would be one thing,” Task Force co-vice chair Albert Siu, MD, told Medscape Medical News. “And, if we found interventions that would be effective in terms of helping individuals with early dementia and their family members to make decisions and plan, we would consider that to be important evidence.”

The Task Force also determined that there is inadequate evidence on nonpharmacologic interventions and on the harms of screening (eg, the impact of labeling and of false-positive results). There is, however, evidence that AChEIs are associated with adverse events, some of which are serious, for example, central nervous system disturbances and arrhythmia.

“Overall, the USPSTF was unable to estimate the balance of benefits and harms of screening for cognitive impairment,” the draft recommendation statement concludes.

The Task Force noted that no professional organization has formal guidelines on screening for dementia or cognitive impairment. However, earlier this year, the Alzheimer’s Association published guidance on the detection of cognitive impairment during the Annual Wellness Visit and recommended an algorithm starting with a health risk assessment, patient observation, and unstructured questioning. Use of a brief structured assessment is recommended if signs or symptoms of cognitive impairment are present or if an informant is unavailable to confirm the absence of signs or symptoms.

Dr. Siu noted that dementia screening for patients showing signs and symptoms of dementia was beyond the scope of the Task Force review. “The scope was what do you do on a population basis for individuals who are not complaining of any symptoms and there have been no signs,” he said. “The question is, should you be automatically screening these people? Certainly, if someone comes in with signs or symptoms, that requires evaluation.”

Dementia affects up to about 5.5 million Americans. Its prevalence increases with age, affecting 5% in those aged 71 to 79 years, 24% in those aged 80 to 89 years, and 37% in those older than age 90 years.

The estimated total health, long-term care, and hospice care costs for dementia in the United States were $183 billion in 2011. These costs don’t include the estimated $202 billion in uncompensated care that informal caregivers provide annually.

“Dementia is a very serious issue that has a significant impact on the lives of older adults and their families,” said Dr. Siu in the press statement. “Although the benefits and harms of what we can offer patients through routine screening are unclear right now, clinicians should remain alert to early signs or symptoms of cognitive impairment and evaluate their patients as appropriate.”

The Task Force is now providing an opportunity for public comment on the draft recommendation until December 2. All public comments will then be considered as the Task Force develops its final recommendation. Dr. Siu expects a final recommendation in the spring of 2014.

“Regardless of what our recommendation is, it will serve as guidance to physicians,” rather than a directive, Dr. Siu told Medscape Medical News.

The Task Force is an independent, volunteer panel of national experts in prevention and evidence-based medicine that works to improve the health of all Americans by making evidence-based recommendations about clinical preventive services, such as screenings, counseling services, and preventive medications.

Benefits of Dementia Screening Still Unclear.

Dementia screening instruments, such as the Mini-Mental State Examination (MMSE), can adequately pick up cognitive impairment in the primary care setting, but many of these tools have not been extensively studied, and there’s no empirical evidence that using them improves decision-making or important outcomes, according to a new literature review.

The review authors also suggest that despite decades of research, it’s still unclear whether cognitive or exercise interventions have a clinically significant effect.

The review was published online October 21 in the Annals of Internal Medicine.

No Basis for Routine Screening

Primary care clinicians may fail to recognize cognitive impairment using routine history and physical examination, according to the study authors. Most patients aren’t diagnosed until at least the moderate stage of the disease, they note.

In 2003, the US Preventive Services Task Force (USPSTF) concluded that there was insufficient evidence to recommend for or against routine screening for dementia in older adults. The current review was conducted in an effort to update these recommendations.

The review included 5 key questions:

1.     Does screening for cognitive impairment in community-dwelling older adults in primary care settings improve decision making or patient, family, caregiver or societal outcomes?

2.     What is the test performance of screening instruments to detect cognitive impairment in these elderly patients?

3.     What are the harms of screening?

4.     Do interventions for mild cognitive impairment (MCI) or mild to moderate dementia improve decision-making or outcomes?

5.     What are the harms of interventions for cognitive impairment?

An extensive review of the literature turned up no studies to answer the first question and only 1 study that addressed the third question. The review therefore concentrated on questions 2 (with 55 fair- to good-quality studies), 4 (131 studies), and 5 (66 studies).

Although the new review included twice the number of studies than existing reviews, its findings were generally consistent with previous findings.

Only 12 brief instruments have been assessed more than once in well-designed studies evaluating their ability to detect dementia in primary care–relevant populations. Only 4 studies were of good quality, with the rest having fair quality and various risks of bias.

In this analysis, the MMSE was the best-studied instrument, with pooled estimates across 14 studies resulting in a sensitivity of 88.3% and a specificity of 86.2% for the most commonly reported cut points. But the MMSE has the longest administration time and is not available for public use without cost, said the authors.

The Clock Drawing Test, Mini-Cog, Memory Impairment Screen, Abbreviated Mental Test, Short Portable Mental Status Questionnaire, Free and Cued Selective Reminding Test, 7-Minute Screen, and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) are available for public use in primary care settings but have been studied only in English.

Most of these instruments can have an acceptable test performance, but not much evidence supported their use, with reproducibility in primary care populations limited and optimum cut-points unknown, according to the authors.

Only 6 instruments were used in more than 1 study assessing diagnostic accuracy to detect MCI in primary care populations. Overall, the sensitivity for detecting MCI for each of these instruments, except for the IQCODE, was lower than that for detecting dementia.

Screening Harmful?

The reviewers identified 1 systematic review and 118 trials that addressed the benefits of the treatment or management of mild to moderate dementia, MCI, or both. Most trials (90%) were of fair quality. Medication trials were exclusively or partially industry funded.

The review included a well-conducted systematic review of US Food and Drug Administration–approved medications for the treatment of Alzheimer’s disease that included 39 randomized controlled trials of acetylcholinesterase inhibitors (AchEIs), as well as 9 additional randomized controlled trials.

Overall, on the basis of these fair- to good-quality trials, AchEIs can improve cognitive function and global functioning in the short term, but the pooled magnitude of these changes is small, with a change of about 1 to 3 points on the Alzheimer`s Disease Assessment Scale-Cognitive Subscale (ADAS-cog).

“The average effect of these changes may not be clinically meaningful as defined using commonly accepted values,” the authors write.

It’s still unclear whether AchEIs can improve physical functioning “given the inconsistent and sparsely reported findings,” they add.

On the basis of 10 fair- to good-quality trials of memantine, a drug approved for moderate to severe AD that has also been evaluated in patients with mild to moderate dementia or MCI, this agent had a benefit similar to that seen with AchEIs on global cognitive functioning in patients with moderate dementia.

These small average effects of change in cognitive function with AchEIs and memantine must be balanced by common adverse effects associated with them, the authors note.

None of the trials of other medications or dietary supplements, including low-dose aspirin, nonsteroidal anti-inflammatory drugs, and vitamins, found a benefit on cognitive or physical function in people with mild to moderate dementia or MCI.

The review found no studies to substantiate or refute concerns about harms of screening. However, the authors said that the harms of screening are poorly studied.

“Some have argued that these harms are minimal, whereas others have argued that the harms of screening and mislabeling persons with dementia are real given the variation in practice of diagnostic confirmation of disease. If broader adoption of screening for cognitive impairment is implemented, it would be wise to better understand these tradeoffs.”

Caregiver Burden

Overall, in trials of interventions targeting caregivers, there was generally a consistent finding of small benefit on caregiver burden and caregiver depression outcomes.

Pooled analyses of 24 trials showed a small but statistically significant effect (standardized mean difference, –0.23 [95% confidence interval (CI)], –0.35 to –0.12l) on caregiver burden. And pooled analyses of 30 trials showed a small but statistically significant effect (standardized mean difference of 0.21 [95% CI, –0.30 to –0.13]) on caregiver depression.

“The clinical meaning of these changes in caregiver burden and depression are, on average, probably small at best,” the authors write.

As well, the authors pointed out that many of the studies of complex interventions for caregivers were conducted outside the United States and may not be freely available.

There was limited reporting of findings for outcomes such as global stress or distress, anxiety, and health-related quality of life for caregivers.

Although evidence is limited and findings inconsistent, cognitive stimulation with or without cognitive training seemed to improve global cognitive function at 6 to 12 months for patients with MCI or dementia. However, the authors add, “the certainty and magnitude of effect of cognitive stimulation is still unclear.”

Exercise interventions also have limited evidence to support their use in patients with MCI or mild or moderate dementia. However, 3 of the better-conducted trials did suggest a benefit of exercise in global cognitive function or physical functioning and health-related quality of life.

The review did not address several important aspects of screening test performance, including the psychometric properties of testing other than sensitivity and specificity.

According to expert consensus guidelines, early detection of cognitive decline may lead to optimal medical management and ultimately lead to improved patient outcomes and reduced costs, but there is little or no empirical evidence to support this, the authors concluded.

“How and whether clinician decision-making and patient and family decision-making are affected by earlier identification of cognitive impairment or earlier management of patients with dementia and their caregivers are important aspects to understand in order to better manage this rapidly growing health care problem,” they write.

Research comparing which criteria — for example, age, comorbid conditions, or functional status — should lead primary care clinicians to perform cognitive assessment is much needed, the authors add. Additional evaluation of brief instruments in more representative populations is also needed.

Right Decision

Commenting on the review for Medscape Medical News was Malaz Boustani, MD, chief operating officer, Indiana University Center for Innovation and Implementation Science and chief innovation and implementation officer, Indiana University Health, Indianapolis.

Dr. Boustani’s research team, with support from the National Institute on Aging, is conducting the first randomized controlled trial to evaluate the benefit and harm of dementia screening in primary care. The trial has now enrolled more than 500 patients (of an eventual target of 4000) and final results are expected in 2017.

According to Dr. Boustani, the USPSTF decision not to recommend routine screening for dementia in primary care was the right one.

“The required data to make such an important and vital decision is not there yet,” he said.

J. Riley McCarten, MD, associate professor, Department of Neurology, University of Minnesota Medical School, medical director, Geriatric Research, Education and Clinical Center (GRECC), and medical director, The Memory Clinic, University of Minnesota Medical Center, Minneapolis, believes that the time for screening has arrived.

“We have the tools to identify dementia and to intervene” in what is a costly and rapidly growing major health care problem, said Dr. McCarten. “To successfully address this tragedy, we must first make diagnosing it a priority.”

Dr. McCarten took issue with the study authors’ conclusion that although screening can identify people with dementia, no empirical evidence exists to determine whether interventions affect decision-making. “Pretending that knowing whether someone has dementia has no effect on decision-making is illogical—and dangerous,” he said.

It’s impossible to “uncouple” identifying dementia—in this case, through screening—from decision-making about dementia, said Dr. McCarten. “Once dementia is identified, decisions are made based on that knowledge.”

Screening identifies patients for whom an intervention is needed, and the intervention necessarily involves decision-making specific to each patient, provider, and family, added Dr. McCarten. “We end up comparing a variety of interventions based on decisions made by and for persons with known dementia.”


Study Shows Higher Rate of Unruptured Cerebral Aneurysm.

A large survey of adult residents of China has determined that the prevalence of unruptured cerebral aneurysms (UCAs) is 7%, that UCAs increase with age, and that they seem to be more common in women.

This prevalence rate is higher than in previous research, in some cases more than twice as high, probably at least in part because researchers used high-resolution magnetic resonance angiography (MRA) to detect UCAs, said lead author Ming-Hua Li, MD, PhD, professor and chairman of Neuro-radiology, Shanghai Jiao Tong University, China.

Of these, though, only about 8.7% were judged to be at any imminent risk for rupture, they note.

The study was published in the October 15 issue of the Annals of Internal Medicine.

High Diagnostic Accuracy

This new analysis included 4813 residents aged 35 to 75 years from 2 Shanghai districts: Changning, an economically well-developed urban area, and Zhabei, a less developed suburban area. This age group represents the range that is most clinically significant in terms of screening, said Dr. Li. Those younger than 35 years are less likely to have UCAs and those older than 75 have a shorter life expectancy, he said.

Participants completed a standard questionnaire to provide demographic information, personal and family medical history, and lifestyle risk factors, and they underwent a physical examination.

The researchers used 3-dimensional (3D) time-of-flight MRA with a voxel size of less than 0.7 mm. To evaluate UCAs, they applied 3D volume rendering and single artery highlighting. This imaging modality was proven in a previous study by the same research group to have very high diagnostic accuracy for detecting intracranial aneurysms compared with 3D digital subtraction angiography (DSA), said Dr. Li.

In the current study, 3 radiologists who were blinded to participants’ information determined the location and size of the UCAs.

UCAs were defined as abnormal focal dilatations of a cerebral artery with attenuation of the vessel wall or an infundibulum in patients without a history of subarachnoid hemorrhage (SAH). Aneurysms were categorized as less than 3 mm, 3 mm to less than 5 mm, 5 mm to less than 10 mm, or 10 mm or more.

The survey excluded UCAs with a diameter of less than 2 mm because, as Dr. Li explained, aneurysms with such a small diameter are difficult to diagnose with the spatial resolution of the imaging modality used.

Aneurysm Sites

Aneurysms were morphologically classified as regular (saccular), irregular (lobular), or fusiform. Sites were classified as internal carotid artery (including the posterior communicating artery), anterior cerebral artery (including the anterior communicating artery), middle cerebral artery (including the MI-2 bifurcation), and vertebrobasilar artery.

The researchers found that 130 men and 206 women had UCAs, with excellent interobserver agreement. The prevalence of UCAs was 7.0% (95% confidence interval, 6.3% to 7.7%).

This is a higher prevalence than in other studies, probably because the researchers used 3D high-resolution MRA, which enabled them to detect small UCAs, Dr. Li speculated. “Those small UCAs could possibly be missed on 2D invasive angiography due to overlapping,” he said. “In addition, we excluded volunteers younger than 35, who are less likely to have UCAs. This could potentially lead to higher prevalence in our survey compared to studies with a wider age range.”

The prevalence of unruptured UCAs in North America is still unknown, said Dr. Li.

The prevalence was higher in women (8.6%) than in men (5.5%) (P < .001). “We hypothesized that decreases in estrogen concentration and estrogen-receptor density may contribute to an increased risk of cerebral aneurysm development in women,” said Dr. Li.

The prevalence of UCAs increased with age and peaked at ages 55 to 64 years in both men and women. This, said Dr. Li, is in line with a meta-analysis published in Lancet Neurology in 2011.

The majority (90.2%) of the UCAs were less than 5 mm in diameter. The mean maximum diameter of the aneurysm sac was 3.5 mm, and the diameter was larger in women.

Most aneurysms (81%) were located in the internal carotid artery (ICA), with more than half (53.9%) in the C5–C6 segments of the ICA. A possible explanation for this, said the authors, is that the study excluded ruptured aneurysms, which are most often located in the anterior or posterior communicating arteries. In addition, the MRA technology allowed for visualization of more UCAs in the siphon segment of the internal carotid artery.

The researchers found that 8.7% of the detected lesions were potentially risky in that they were large, lobulated aneurysms or grew during follow-up and so may have been prone to rupture.

The patients with these aneurysms potentially in danger of rupture are being followed closely, said Dr. Li. “We currently follow up those patients annually by 3D MRA if the lesions remain stable — so no growth or daughter-sac formation. If lesion growth is detected at follow-up, we suggest further treatment accordingly.”

The study did not show an association between the prevalence of aneurysms and hypertension or cardiovascular disease. This was a cross-sectional study that mainly focused on the prevalence of UCAs, explained Dr. Li, adding that the association between risk factors such as hypertension and cardiovascular disease and development of UCAs in Chinese adults needs to be explored in other longitudinal studies.

The findings may not apply to the general population or to populations outside of China, said the authors.

No Higher

R. Loch Macdonald, MD, PhD, Keenan Endowed Chair in Surgery and head, Division of Neurosurgery, St. Michael’s Hospital, and professor of surgery, University of Toronto, Ontario, Canada, who has a special research interest in cerebral aneurysms, doesn’t believe that the prevalence of aneurysms is any higher in China than elsewhere in the world.

“I suspect they are not more common compared to other geographic regions and ethnicities or races and that the difference is due to a selected older population and more sensitive screening test,” used in the current study, said Dr. Macdonald when approached by Medscape Medical News for a comment.

He pointed to a previously published meta-analysis that found 3% of the population harbored an aneurysm, adjusted to a population with a mean age of 50 years that was 50% male, and expanded on why the numbers in the current study might be much higher.

“They may have found a higher incidence due to inclusion of only patients aged 35 to 75 years,” he added. “Second, the distribution of aneurysms includes many more very small proximal carotid aneurysms. These may not have been diagnosed as frequently before by other methods, so this new screening study may have detected more due to increased sensitivity of the screening method.”

Doctors Asked to Counsel Teens About the Dangers of Smoking.

Doctors already have a hefty checklist of topics to go over with their patients. Will they be able to squeeze in discussions about the health hazards of tobacco during office visits?

The recommendation, published in the Annals of Internal Medicine and Pediatrics, that primary-care physicians start counseling younger patients about tobacco updates the U.S. Preventive Services Task Force (USPSTF) advice from 2003. At that time, the task force of experts could not find enough evidence to ask physicians to intervene with talks about tobacco during checkups with teens and adolescents. Since then, however, the panel says more studies have shown that conversations with physicians can have an impact in reducing smoking and other tobacco use among teens.


The members analyzed trials that were designed to either prevent smoking among adolescents or to encourage them to quit. Youngsters who were told about antitobacco programs by their primary-care physicians were 19% less likely to start smoking than peers who were not provided with such information. Compared with other methods such as group sessions to discuss the health risks of tobacco; videos and pamphlets that provided information on tobacco; or even prescription forms preprinted with antitobacco messages, having conversations with health care professionals, either in the doctors’ office or over the phone, appeared to be the most effective.

That’s encouraging for physicians who have long struggled to help adult smokers to quit. “We now know that the smokers that have the most difficulty quitting are the smokers that start in their teenage years and smoke into young adulthood. Those are the smokers that may never be able to quit smoking, and that’s recent data,” says Dr. Len Horovitz, an internist and pulmonary specialist at Lenox Hill Hospital in New York City, who was not on the panel. “It seems incumbent upon pediatricians and internists who have experience with these patients to counsel those patients at exactly that time.”

Rates of cigarette smoking among teens have stalled, but that doesn’t mean they aren’t still using tobacco. Some have switched to cigars, which are less expensive, often flavored, and even crafted to look like cigarettes. While teen tobacco use dropped significantly in the U.S. between the years 1997 and 2003, beginning in the early 2000s, these declines started to reverse as states cut funding for tobacco-control programs. From 2009 to ’11, tobacco use remained steady, with about 1 in 5 high school students using some form of tobacco.

(MORE: Secondhand Smoke Is More Damaging for Teen Girls Than Boys)

Will the USPSTF recommendation help bring tobacco use down again? Already pressured to cover a significant amount of health information in a short office visit, Horovitz says doctors may find it difficult to throw another important health issue into the mix. “There’s counseling on diet, exercise, fastening your seat belt [and] nutrition; and smoking cessation measures are a part of the annual physical too,” he says. To make time for discussions about such lifestyle factors and how they affect their health, Horovitz says he allots an hour for each such visit.

Discussing such lifestyle behaviors, including tobacco use, is easier if doctors and patients have a long-standing relationship that is built on trust and familiarity. “All patients will talk about stress, and I ask questions that are pointed enough that they will volunteer that information. When you take care of a patient over a few years, there is trust and confidence in the doctor-patient relationship, and the patient will be more spontaneous in giving you facts that they might not give a doctor at first or if they don’t have a consistency in who they see,” says Horovitz.

Since not all patients have such interactions with their doctors, the task force also identified some other strategies that could help physicians to help their teen tobacco users to quit. For instance, some cessation programs send reminder text messages to teens’ smartphones, while some states, including New York and Rhode Island, have gone after their wallets by increasing the price of cigarettes. Mass-media antismoking campaigns and laws that target retailers selling cigarettes to underage customers are also effective. In an editorial accompanying the new recommendations, Dr. Michael Steinberg of Robert Wood Johnson University Hospital and Cristine Delnevo of the Rutgers School of Public Health also argue for raising the smoking age from 18 to 21, since that would make it much harder for younger people to purchase tobacco products and therefore discourage them from smoking regularly.

With the new recommendation, doctors are being asked to join antitobacco efforts for teens, based on the latest data that suggests they can have a significant impact on whether or not their young patients smoke. It’s just a matter of finding the time to discuss how smoking and tobacco can affect teens’ health, and making such conversations a priority during the office visit.