Older heart patients need personalized preventive care

Strategies to prevent heart attack, stroke and other major cardiac events should be individualized for older adults who should play a role in choosing their therapies, according to an American Heart Association scientific statement published in its journal Circulation.

31 oct 2013--The statement is a comprehensive review of the benefits and risks of medical and lifestyle interventions for cardiovascular disease patients age 75 and older. It addresses obesity, high blood pressure, cholesterol, diabetes, inadequate nutrition, physical inactivity and tobacco use. It also includes the value of cardiac rehabilitation, revascularization techniques and implantable cardioverter defibrillators.

"Preventive care should not be set aside simply because you're getting older," said Daniel Forman, M.D., co-lead author of the statement and director of Cardiac Rehabilitation at Brigham and Women's Hospital in Boston.

The statement is published at a critical time when about 6 percent of the U.S. population (about 18.6 million) is 75 and older. That percentage is expected to double by 2050. More people are living with cardiovascular disease, but many are not receiving evidence-based therapies.

Statement highlights include:

• While some interventions result in modest survival gains in older people, they provide other benefits. For example, weight loss may not lower the risk for a cardiovascular event, but it can improve mobility, blood sugar control and arthritic pain.
• Doctors must consider drug interactions, adherence, medication costs and other consequences for older patients who take multiple medications for heart-related and other conditions.
• Patient preferences should be carefully evaluated. Some older patients may prefer to live with an increased risk of a cardiovascular event rather than make lifestyle changes or undergo procedures late in life.
• Healthcare providers should ask patients if they're using "alternative medicine" products, such as herbs, foods or nutrition supplements. Clinical trials have not supported their use, but it's common among older patients and can have negative interactions with prescription drugs. To ensure older adults with cardiovascular disease receive the most appropriate care, the statement also advises:
• More research to clarify which lifestyle changes, medication regimens and revascularization and device strategies provide the greatest benefits and fewest risks.
• Better risk assessment tools to determine which patients are most likely to benefit from preventive therapy.
• Improved health literacy among older adults to ensure they understand the advantages, burdens and limitations of care.

"Care for older adults demands equally rigorous thought as for a younger adult," Forman said.

Provided by American Heart Association

Results from many large clinical trials are never published

A new analysis of 585 large, randomized clinical trials registered with ClinicalTrials.gov finds that 29 percent have not been published in scientific journals. In addition, nearly 78 percent of the unpublished trials had no results available on the website, either.

30 oct 2013--As a result, nearly 300,000 people who were enrolled in the 171 unpublished trials "were exposed to the risks of trial participation without the societal benefits which accompany the dissemination of trial results," said Christopher W. Jones, MD, a former resident physician at University of North Carolina School of Medicine who is now an attending physician at Cooper Medical School of Rowan University in Camden, N.J. and lead author of the study published in the Oct. 29, 2013 issue of the British Medical Journal.

Non-publication of clinical trials has been a controversial issue in recent years. In particular, industry-funded clinical trials – such as those paid for by pharmaceutical companies – have come under fire on allegations that such trials are often not published when the results are not favorable to the drug or other product being tested.

Against this background, the study authors set out to determine what happened to 585 large, randomized trials with at least 500 participants that were registered with ClinicalTrials.gov and completed before January 2009. ClinicalTrials.gov is a website that provides patients, their family members, health care professionals, researchers and the public with easy access to information on publicly and privately supported clinical studies on a wide range of diseases and conditions.

Of the 585 registered trials, 171 (29 percent) had not been published by November 2012, when the final literature search for this study was conducted. Non-publication was more common among trials that received industry funding (32 percent ) compared to those without industry funding (18 percent). Of the 171 unpublished trials, 133 (78 percent) had no results available in ClinicalTrials.gov.

"Clinical trials are an essential source of information for how to care for patients. Additional policies are needed to ensure that results of all large clinical trials are made publicly available in a timely manner," said Timothy F. Platts-Mills, MD, an assistant professor of emergency medicine at UNC and senior author of the study.

Provided by University of North Carolina Health Care

DIY and gardening can cut heart attack, stroke risk by 30 percent and prolong life in 60+ age group

A spot of DIY or gardening can cut the risk of a heart attack/stroke and prolong life by as much as 30 per cent among the 60+ age group, indicates research published online in the British Journal of Sports Medicine.

29 oct 2013--These routine activities are as good as exercise, which is ideal for older people who don't often do that much formal exercise, say the researchers.

They base their findings on almost 4000 sixty year olds in Stockholm, Sweden, whose cardiovascular health was tracked for around 12.5 years.

At the start of the study, participants took part in a health check, which included information on lifestyle, such as diet, smoking, and alcohol intake, and how physically active they were.

They were asked how often they had included a range of daily life activities, such as gardening, DIY, car maintenance and blackberry picking over the previous 12 months, as well as whether they had taken any formal exercise.

Their cardiovascular health was assessed by means of lab tests and physical examinations, to check on blood fats, blood sugars, and blood clotting factor, high levels of which are linked to a raised heart attack and stroke risk.

At the start of the study, those who had a generally active daily life had a much lower risk profile for cardiovascular problems, irrespective of how much formal exercise they took, than those with low levels of daily activity.

This profile included smaller waists, lower levels of potentially harmful blood fats, and lower gluose, insulin, and clotting factor levels in men.

The same was true of those who did a lot of formal exercise, but who weren't routinely physically active very often. Those who exercised regularly and were also often physically active had the lowest risk profile of all.

During the 12.5 year monitoring period, 476 of the participants had their first heart attack and 383 died from various causes.

The highest level of daily physical activity was associated with a 27% lower risk of a heart attack or stroke and a 30% reduced risk of death from all causes, compared with the lowest level, irrespective of how much regular formal exercise was taken in addition.

"Our findings are particularly important for older adults, because individuals in this age group tend, compared to other age groups, to spend a relatively greater proportion of their active day performing [routine activities] as they often find it difficult to achieve recommended exercise intensity levels," say the authors.

They suggest that the biological explanations for their findings might lie in energy expenditure: prolonged sitting drives down metabolic rate to the bare minimum, while standing up and physical activity increase it.

Muscular contractions may also provide some clues. Sitting down doesn't require any muscle effort, which can disrupt the skeletal muscle's normal hormone production, with potential adverse effects on other body organs and tissues.

More information: The importance of non-exercise physical activity for cardiovascular health and longevity, Online First,

Provided by British Medical Journal

Beta-blockers may increase adverse cardiac events, patients at risk during noncardiac surgical procedure

A recent study shows that patients given beta-blockers may actually be at increased risk of having an adverse cardiac event during a noncardiac surgical procedure. Risk of irregular heartbeat and worsening of symptoms in patients with existing heart disease also seemed to increase, but to a lesser degree. Beta-blockers are drugs commonly prescribed to treat high blood pressure and congestive heart failure. The study was presented during CHEST 2013, the annual meeting of the American College of Chest Physicians (ACCP), held October 26-31 in Chicago.

29 oct 2013--Researchers at State University of New York (SUNY)-Upstate Medical University Hospital analyzed 755 patients who had undergone noncardiac surgery in a single university-based center, with patients randomly chosen and subclassified according to gender, ethnicity, risk of surgery, and whether beta-blockers were used before, during, or after a noncardiac surgical procedure. Six different outcomes were investigated in the study: all-cause mortality, acute coronary syndrome (ACS), irregular heartbeat, cardiac event-related death, worsening of symptoms in a patient who has existing heart disease, and slower-than-normal heart rate. Three variables were used to predict these outcomes: beta-blocker administration, revised cardiac index score (RCRI)—a prediction of assessing risk of cardiac complications, and risk of surgery. Beta-blocker use was found to increase the odds of having an acute coronary event.

"The results from this study become especially important in view of the fact that beta-blockers are currently recommended by the American College of Cardiology/American Heart Association (ACC/AHA) 2011 guidelines regarding cardiac risk and management before, during and after surgery," said David D. Gutterman, MD, FCCP and past president of the ACCP.

Provided by American College of Chest Physicians

Rheumatoid arthritis and heart disease: Studies shed light on dangerous connection

People with rheumatoid arthritis and other chronic inflammatory conditions are at higher risk of heart disease. Who is in the most danger, why and how best to prevent and detect cardiovascular complications are important questions for physicians and researchers. Mayo Clinic studies presented at the American College of Rheumatology annual meeting shed new light on this connection, in part by revealing factors that seem to put some rheumatoid arthritis patients in greater jeopardy of heart problems: early menopause, more severe rheumatoid arthritis and immunity to a common virus, cytomegalovirus, among others.

28 oct 2013--In one study, Mayo researchers discovered that patients whose rheumatoid arthritis is more severe are likelier to have heart problems. That becomes true soon after rheumatoid arthritis strikes, making early treatment of rheumatoid arthritis important, says co-author Eric Matteson, M.D., chair of rheumatology at Mayo Clinic in Rochester, Minn.

"One thing that we learned in particular in this study is that the high disease burden on the joints in the first year of disease already is a very strong predictor of cardiovascular disease subsequently, and that seems to be mitigated as time goes on if the disease burden can be reduced too," Dr. Matteson says.

In other research, a Mayo team looked at a common virus called cytomegalovirus, a bug many people get and do not even know they have. They found correlations between rheumatoid arthritis patients' immune response to the virus and the development of myocardial disease.

If it turns out that there is this relationship, then it may be that one way to spot patients who are at higher risk for heart disease would be an immune profile or biomarkers related to the cytomegalovirus and its associated immune activation signaling," says Dr. Matteson, a co-author.

Another study found that women with rheumatoid arthritis and early menopause—menopause before age 45—also seem to be at higher risk of heart disease. About two-thirds of patients with rheumatoid arthritis are women, and researchers have long studied possible hormonal influences on development of the disease, Dr. Matteson says.

"This study shows the complex relationship between rheumatoid arthritis, hormones and heart disease," says Dr. Matteson, the senior author. "We also found patients who have had multiple children, especially seven or more, are at higher risk of cardiovascular disease compared with women who have menopause at a normal age or have fewer children."

Provided by Mayo Clinic

Flu vaccine associated with lower risk of cardiovascular events

Receiving an influenza vaccination was associated with a lower risk of major adverse cardiovascular events such as heart failure or hospitalization for heart attack, with the greatest treatment effect seen among patients with recent acute coronary syndrome (ACS; such as heart attack or unstable angina), according to a meta-analysis published in the October 23/30 issue of JAMA.

27 oct 2013--"Among nontraditional cardiovascular risk factors, there remains interest in a potential association between respiratory tract infections, of which influenza and influenza-like illnesses are common causes, and subsequentcardiovascular events," according to background information in the article. Several epidemiological studies have suggested a strong inverse relationship between influenza vaccination and the risk of fatal and nonfatal cardiovascular events.

Jacob A. Udell, M.D., M.P.H., F.R.C.P.C., of the University of Toronto, and colleagues conducted a meta-analysis of all randomized clinical trials (RCTs) of influenza vaccine that studied cardiovascular events as efficacy or safety outcomes to determine if influenza vaccination is associated with prevention of cardiovascular events. The researchers identified five published and 1 unpublished RCTs of 6,735 patients (average age, 67 years; 51 percent women; 36 percent with a cardiac history; average follow-up time, 7.9 months) that met inclusion criteria for the study. Analyses were stratified by subgroups of patients with and without a history of acute coronary syndrome(ACS) within 1 year of randomization.

In the 5 published RCTs, 95 of 3,238 patients treated with influenza vaccine (2.9 percent) developed a major adverse cardiovascular event compared with 151 of 3,231 patients (4.7 percent) treated with placebo or control within 1 year of follow-up, an absolute risk difference favoring flu vaccine of 1.74 percent. The addition of the unpublished data did not materially change the results (2.9 percent influenza vaccine vs. 4.6 percent placebo or control).

In a subgroup analysis of 3 RCTs of patients with pre-existing coronary artery disease (CAD), the risk of major adverse cardiovascular events among patients with a history of recent ACS was especially lower with vaccine (10.3 percent influenza vaccine vs. 23.1 percent placebo or control), an absolute-risk difference of 12.9 percent, compared to patients with stable CAD (6.9 percent influenza vaccine vs. 7.4 percent placebo or control). Results were similar with the addition of unpublished data.

"Within this global meta-analysis of RCTs that studied patients with high cardiovascular risk, influenza vaccination was associated with a lower risk of major adverse cardiovascular events within 1 year. Influenza vaccination was particularly associated with cardiovascular prevention in patients with recent ACS. Future research with an adequately powered multicenter trial to confirm the efficacy of this low-cost, annual, safe, easily administered, and well-tolerated therapy to reduce cardiovascular risk beyond current therapies is warranted," the authors conclude.

In an accompanying editorial, Kathleen M. Neuzil, M.D., M.P.H., of PATH, Seattle, discusses the importance of improving influenza vaccination coverage.

"There are proven ways to increase vaccination coverage, including expanding access through nontraditional settings (e.g., pharmacy, workplace, school venues), improving the use of evidence-based practices at medical sites (e.g., standing orders, reminder or recall notification), and using immunization registries. One of the most consistent and relevant findings of operational research is that recommendation for vaccination from physicians and other health care professionals is a strong predictor of vaccine acceptance and receipt among patients. While few are in a position to develop new influenza vaccines, all health care practitioners can recommend influenza vaccine to their patients. Doing so will help achieve the goal of 100 percent vaccination for the 2013-2014 influenza season."

More information: DOI: 10.1001/jama.2013.279206
DOI: 10.1001/jama.2013.279207

Provided by The JAMA Network Journals

Lithium in drinking water reduces suicide rates – possibly also as a result of medicine residue

A study carried out back in June 2011 at the MedUni Vienna has shown that lithium contained in drinking water could reduce suicide rates. Previously, researchers had assumed that the majority of this lithium came from natural sources, leached out of rocks and stones. According to Nestor Kapusta from the University Department of Psychoanalysis and Psychotherapy at the MedUni Vienna, new data has indicated that residue from prescribed lithium medication is finding its way into aquifers.

26 oct 2013--Says Kapusta: "The light metal lithium has been used in psychiatry for 60 years as a mood stabiliser and to prevent depression. It is also excreted out of the body and enters the groundwater or is not filtered out by the sewage treatment plants." The psychiatrist predicts that regions with high lithium prescribing rates may have a type of "cohort protection" in place: "A high density of psychiatrists and high levels of prescribing could mean more lithium in the drinking water, which could also have a positive impact on untreated individuals." Jakob Klein from the Suicide Research Group at the MedUni Vienna is currently working on this study.

High lithium levels in drinking water means lower suicide rate

Even in the study carried out two years ago based on 6,460 samples of drinking water in 99 Austrian districts, it was discovered that high lithium levels in drinking water tended to produce a lower suicide rate in that area. This indicates that lithium can have measurable effects even as a trace element. Says Kapusta: "Some researchers now even maintain that lithium could be essential for humans."

A current study in the USA has demonstrated contamination of the groundwater and drinking water from the tap with numerous types of medication residue, illustrating how seriously the build-up of drugs in drinking water needs to be taken. Says Kapusta: "In the case of lithium, this would produce a potentially positive effect. However it would be far too premature to suggest that lithium should be added to drinking water. Further research is definitely needed on this." Although low levels of lithium in drinking water are not expected to cause any side effects compared to therapeutic doses (including kidney and thyroid problems), there are no studies to confirm this.

Says Kapusta: "Lithium is first and foremost not a panacea, even though some reports portray it as such." It has been discovered, for example, that lithium has a positive effect on the growth of new brain cells not just in adults, but also in embryos. It is however not yet clear what effect long-term exposure to the trace element can have on pregnant women and children. This would require urgent fundamental research, discouraging any thoughts of supplementation for the time being, says the MedUni Vienna expert.

Lithium could also be of significance in the treatment of Alzheimer's disease or dementia: the element appears to deposit itself in the brain, more in the white matter than in the grey matter. Conversely, it is known that people receiving lithium treatment produce more grey matter. "Alzheimer's disease can be associated with the destruction of and changes to white matter that lithium could help to counteract," says the MedUni Vienna researcher.

Provided by Medical University of Vienna

Avicenna's Medicine

An ancient Arabic medical encyclopedia written in the eleventh century provides a model for practicing individualized medicine, says a Georgetown University Medical Center (GUMC) scientist who, with two colleagues, has translated the original text into English. Credit: Hakima Amri, PhD, Marc Micozzi, MD, PhD and Mones Abu-Asab, PhD

An ancient Arabic medical encyclopedia written in the eleventh century provides a model for practicing individualized medicine, says a Georgetown University Medical Center (GUMC) scientist who, with two colleagues, has translated the original text into English.

25 oct 2013--The "Canon of Medicine," written by the Persian scholar ibn Sīnā (Latinized as Avicenna), is the definitive work of Unani medicine, which is based on the teachings of the Greek physician Hippocrates and the Roman physician Galen. The "Canon" was further developed into a systems approach to health by Arab and Persian physicians.

"Earlier translations were not carried out directly from the original Arabic text; they deviated from that text and contain inaccuracies," says Georgetown's Hakima Amri, PhD, an associate professor in the department of biochemistry, cellular and molecular biology.

"Avicenna's Medicine—A New translation of the 11th-Century Canon with Practical Applications for Integrative Health Care" was published in July by Amri, Marc Micozzi, MD, PhD, an adjunct professor of pharmacology and physiology at GUMC, and Mones Abu-Asab, PhD, a senior scientist at the National Institutes of Health.

Avicenna's medical writings aimed to rid medicine of superstition and base it on empirical observation, objectivity and rationalism, Amri says.

"Avicenna established the six essential requirements for health as fresh clean air, food and drink, movement and rest, sleep and wakefulness, eating and exercise, and healthy mental state," she explains. These are the prerequisites for healthy living and preventive medicine as emphasized by today's physicians, Amri points out.

"He also declared that health parameters should be considered according to race, gender, age and geographical adaptation," she adds. "This is what physicians today are discussing when talking about personalized medicine. It is only in the last decade that the medical community reported that men and women could present different symptom constellations."

Amri says the new book provides commentary and explanations not included in other texts, such as translating the body's four "humors" and "temperaments" into modern-day medical terminology.

Humors refer to biomolecules such as proteins, lipids, organic acids and other macromolecules, and temperaments often refer to energy production and hydration balance in cells and tissues—concepts known today as homeostasis and allostasis, says Amri.

Given that understanding, she says, "as scientists, we are finding the biomedical knowledge of today is proving the insights into health and disease detailed in the 'Canon.'"

Amri dedicates the book to "the continuum of people who have kept alive the quest for knowledge over thousands of years."

She says, "The 'Canon' set the stage for Western medicine and could provide a paradigm to our systems medicine, a framework to personalized medicine, and a foundation to preventive medicine and integrative health, today."

About Georgetown University Medical Center

Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis—or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health.

Provided by Georgetown University Medical Center

USPSTF: Evidence lacking for cognitive impairment testing

24 oct 2013—Screening instruments can detect dementia but there is insufficient evidence to determine the clinical effect of screening and interventions, according to a review conducted for the U.S. Preventive Services Task Force and published online Oct. 22 in the Annals of Internal Medicine.

Jennifer S. Lin, M.D., from Kaiser Permanente Northwest in Portland, Ore., and colleagues conducted a systematic literature review to examine the diagnostic accuracy of cognitive screening instruments and the benefits and harms of interventions for early cognitive impairment.

Based on the findings, the researchers note that the most thoroughly studied instrument was the Mini-Mental State Examination, which is not available without cost. Publicly available instruments that have adequate performance for detecting dementia include the Clock Drawing Test, the Mini-Cog, the Memory Impairment Screen, and the Short Portable Mental Status Questionnaire. Limited benefit, with unclear clinical relevance, was seen with use of U.S. Food and Drug Administration-approved medications and caregiver interventions. Benefits were also limited by common adverse events and restricted availability of caregiver interventions. Limited evidence was available to support cognitive stimulation and exercise for persons with mild-to-moderate dementia or mild cognitive impairment.

"Whether interventions for patients or their caregivers have a clinically significant effect in persons with earlier detected cognitive impairment is still unclear," the authors write.

More information: Full Text (subscription or payment may be required)

Specialist geriatric medical assessment for patients discharged from hospital acute assessment units: Randomised controlled trial (UK)

22 oct 2013--This individual patient randomised-controlled trial evaluated the effect of specialist geriatric medical management on the outcomes of at risk older people discharged from acute medical assessment units, compared with usual care.

The study was set in 2 hospitals in Nottingham and Leicester, UK, and participants were 433 patients aged 70 or over who were discharged within 72 hours of attending an acute medical assessment unit and at risk of decline as indicated by a score of at least 2 on the Identification of Seniors At Risk tool.

The intervention was an assessment made on the acute medical assessment unit and further outpatient management by specialist physicians in geriatric medicine, including advice and support to primary care services.

Based on the results of the trial, the authors conclude that this specialist geriatric medical intervention applied to an at risk population of older people attending and being discharged from acute medical units had no effect on patients’ outcomes or subsequent use of secondary care or long term care.

This is an open access article and is available to read in free full text at:  http://www.bmj.com/content/347/bmj.f5874

Edmans J ,Bradshaw L ,Franklin M ,Gladman J & Conroy S. (2013). Specialist geriatric medical assessment for patients discharged from hospital acute assessment units: Randomised controlled trial. BMJ:f5874.

Two forms of Parkinson's disease identified

Why can the symptoms of Parkinson's disease vary so greatly from one patient to another? A consortium of researchers, headed by a team from the Laboratoire CNRS d'Enzymologie et Biochimie Structurales, is well on the way to providing an explanation. Parkinson's disease is caused by a protein known as alpha-synuclein, which forms aggregates within neurons, killing them eventually. The researchers have succeeded in characterizing and producing two different types of alpha-synuclein aggregates. Better still, they have shown that one of these two forms is much more toxic than the other and has a greater capacity to invade neurons. This discovery takes account, at the molecular scale, of the existence of alpha-synuclein accumulation profiles that differ from one patient to the next. These results, published on October 10 in Nature Communications, represent a notable advance in our understanding of Parkinson's disease and pave the way for the development of specific therapies targeting each form of the disease.

21 oct 2013--Parkinson's disease, which is the second most frequent neurodegenerative disease after Alzheimer's, affects some 150,000 people in France. According to those suffering from the disease, it can manifest itself in the form of uncontrollable shaking (in 60% of patients) or by less-localized symptoms such as depression, behavioral and motor disorders. These differences in symptoms point to different forms of Parkinson's disease.

This condition, for which no curative treatment currently exists, is caused by the aggregation in the form of fibrillar deposits of alpha-synuclein, a protein that is naturally abundant at neuron junctions. These misfolded alpha-synuclein aggregates propagate between neurons. When they invade a new neuron, they are capable of recruiting normal alpha-synuclein and adding it to the deposit. For this reason, many researchers advocate that the alpha-synuclein of the aggregates should be considered as an infectious protein, in other words a prion. Highly toxic, the alpha-synuclein deposits end up by triggering a process of apoptosis, i.e. cell death.

The researchers have shown that there is not just one single type of aggregate. They succeeded in producing two types of aggregate that only differ in how the protein stacks up. At the millionth of a millimeter scale, the first form of aggregate resembles spaghetti, whereas the second form is long and flat, recalling the shape of wider pasta such as linguine. The team of scientists then tried to determine whether these structural differences result in functional differences. To find out, they placed the two types of aggregates in contact with neuronal cells in culture. They discovered that the capacity of the "spaghetti" form to bind to and penetrate cells is notably greater than that of the "linguine" form. The "spaghetti" form is also considerably more toxic and rapidly kills the infected cells. This form has shown itself to be capable of resisting the cell mechanisms responsible for eliminating it, whereas the "linguine" form is, to a certain extent, controlled by the cell.

The researchers are convinced that the existence of at least two forms of alpha-synuclein aggregates explains why doctors are faced with different Parkinson's diseases depending on the patient. Experiments on mice are currently underway to confirm this hypothesis. Furthermore, the scientists consider that analysis of the type of aggregate could lead to an efficient diagnosis method, which would make it possible in particular to assess the virulence of the disease for each patient. Finally, they hope that by refining the characterization of the structure of the aggregates, it will be possible to develop targeted therapeutic strategies for each variant in order to slow down the propagation of abnormal alpha-synuclein within the brain.

More information: Bousset, L. et al. Structural and functional characterization of two alpha-synuclein strains, Nature Communications, 10 October 2013. DOI: 10.1038/ncomms3575

Provided by CNRS

Blood pressure drugs shown to decrease risk of Alzheimer's disease dementia

A Johns Hopkins-led analysis of data previously gathered on more than 3,000 elderly Americans strongly suggests that taking certain blood pressure medications to control blood pressure may reduce the risk of dementia due to Alzheimer's disease (AD).

19 oct 2013--In a report published in a recent edition of the journal Neurology, a team of researchers found that people over the age of 75 with normal cognition who used diuretics, angiotensin-1 receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors showed a reduced risk of AD dementia by at least 50 percent. In addition, diuretics were associated with 50 percent reduced risk in those in the group with mild cognitive impairment.

Beta blockers and calcium channel blockers did not show a link to reduced risk, the scientists reported.

"Identifying new pharmacological treatments to prevent or delay the onset of AD dementia is critical given the dearth of effective interventions to date," says the author, Sevil Yasar, M.D., Ph.D., assistant professor of medicine in the Department of Geriatric Medicine and Gerontology at the Johns Hopkins University School of Medicine. "Our study was able to replicate previous findings, however, we were also able to show that the beneficial effect of these blood pressure medications are maybe in addition to blood pressure control, and could help clinicians in selecting an antihypertensive medication based not only on blood pressure control, but also on additional benefits."

Alzheimer's disease is a rapidly increasing clinical and public health issue in the United States' aging population, and the most common cause of intellectual and social decline.

Yasar and her colleagues conducted a "post-hoc" analysis of information gathered originally in the so-called Ginkgo Evaluation of Memory Study (GEMS) study, a six-year effort to determine if use of the herb ginkgo biloba reduced AD risk. That study , a double-blind, randomized, controlled clinical trial of 3,069 adults without dementia, aged between 75 and 96 years, began in 2000 and recruited participants from four U.S. cities: Hagerstown, Md.; Pittsburgh, Pa.; Winston-Salem/Greensboro, N.C.; and Sacramento, Calif.

Yasar said that while the GEMS trial showed no benefit of ginkgo biloba in reducing incidence of dementia, information was also available among the study participants related to their use of several classes of antihypertensive drugs. Extensive studies suggest that high blood pressure is a major risk factor for dementias including AD, and there had been suggestions that drugs used to control blood pressure conferred a protective effect on the brain in addition to controlling blood pressure.

The question, she said, was which ones were associated with reduced AD dementia risk, and which were not.

Yasar and colleagues looked at 2,248 of the GEMS subjects, of them 351 reported use of a diuretic, 140 use of ARBs, 324 use of ACE inhibitors, 333 use of calcium channel blockers and 457 use of beta blockers. The average age of this group was 78.7 years, and 47 percent were women.

"We were able to confirm previous suggestions of a protective effect of some of these medicines not only in participants with normal cognition, but also in those with mild cognitive impairment," says Yasar.

"Additionally, we were also able to assess the possible role of elevated systolic blood pressure in AD dementia by placing those within each medication group in categories above and below systolic blood pressures of 140 mmHg, the standard cut-off reading for a diagnosis of hypertension," she said.

Yasar cautioned that the analysis had its limitations, owing mostly to the fact that the data collected by the GEMS trial were not gathered to directly measure the effect of the drugs, and by the fact that it was impossible to tell with certainty how well each group of participants complied with their drug treatments. Nor did the research team have information on subjects' use of drugs prior to the study period.

But, she said, "the consistent pattern we saw of reduced risk of AD dementia associated with these medications warrants further studies, including the use of brain imaging, to better understand the biologic basis of these associations." Such studies, she added, "could lead to identification of new pharmacologic targets for preventive interventions to slow cognitive decline and possibly delay progression of AD dementia."

Provided by Johns Hopkins University School of Medicine

Making sense of conflicting advice on calcium intake

In recent years, studies have reported inconsistent findings regarding whether calcium supplements used to prevent fractures increase the risk of heart attack.

18 oct 2013--Now, in an assessment of the scientific literature, reported as a perspective piece in the October 17, 2013 issue of the New England Journal of Medicine, a UC San Francisco researcher says patients and health care practitioners should focus on getting calcium from the diet, rather than supplements, when possible.

"Osteoporosis may result from inadequate calcium intake and it's quite common for certain segments of our population, such as the elderly, to consume less than the recommend amount," said Douglas C. Bauer, MD, UCSF professor of Medicine, Epidemiology and Biostatistics. "But a high calcium diet should be the preferred method to receive adequate amounts of the nutrient. The Institute of Medicine's recommended dosage for post-menopausal women over the age of 50 and men over 70 is 1,200 mg per day.

"If it is not possible to consume enough calcium from the diet, the use of calcium supplements is most likely safe and not associated with cardiovascular outcomes," he said.

Calcium supplements are known to have several side effects, the most common being indigestion and minor constipation, and kidney stones are a rare complication. However, several recent studies have suggested that calcium supplements can also lead to an increase risk of heart attacks.

A 2010 British Medical Journal study, which pooled nearly a dozen randomized trials, concluded that calcium supplements "are associated with an increased risk of myocardial infarction [heart attacks]" and went on to say, " As calcium supplements are widely used, these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population."

A 2013 JAMA Internal Medicine non-randomized study examined 11,778 cardiovascular-related deaths and found an increased risk with calcium supplement use. The authors concluded, "high intake of supplemental calcium is associated with an excess risk of CVD (cardiovascular disease) death in men but not in women."

However, several other studies have shown no relationship between the use of calcium supplements and cardiovascular events.

For example, a 2010 meta-analysis that included all of the Women's Health Initiative (WHI) trial participants showed "no significant relationship between supplementation and cardiovascular events" in three trials of calcium supplements alone.

Bauer recommends consuming dairy products to increase one's dietary intake of calcium as well as food products that are fortified with extra calcium, such as kale, broccoli and Bok Choy.

Dr. Bauer has received research support from Amgen and Novartis in the past for his work on independent adjudication of endpoints in clinical trials unrelated to calcium, which ended two years ago.

Provided by University of California, San Francisco

Single gene may predict mental decline after heart surgery

Preliminary study suggests blood test could help doctors assess patient's risk.

16 oct 2013—A certain gene appears to increase risk for mental decline after heart surgery, a new study suggests.

Between 30 percent and 50 percent of heart surgery patients have a decrease in mental function after heart surgery, but it hasn't been known if this is a side effect of the surgery and anesthesia, or a progression of existing neurologic disease, the researchers said.

Their study included 233 elderly, white patients whose mental function was assessed before heart surgery and five years after.

Those with the APOE4 gene were more likely than those without the gene to experience long-term memory loss, attention problems and difficulty understanding spoken or written words five years after the surgery, according to the study scheduled for presentation Sunday at the annual meeting of the American Society of Anesthesiologists in San Francisco.

"Our findings suggest that the long-term cognitive decline previously seen after surgery is related more to the patient's genetic makeup than to the surgery itself," Dr. Karsten Bartels, who helped conduct this study while a fellow in cardiothoracic anesthesiology and critical care medicine at Duke University Medical Center, said in a society news release.

"Knowing which patients have the APOE4 genotype can help doctors assess the risk for cognitive problems following surgery, ultimately allowing patients to make better-informed decisions and permitting doctors to direct strategies to protect the brain after surgery," he explained.

People are born with the APOE4 (apolipoprotein E4) gene, which can be detected in a blood test. Apolipoproteins play an important role in cholesterol metabolism and inflammation.

APOE4 has been shown to increase the risk of developing Alzheimer's disease.

Data and conclusions presented at medical meetings are typically considered preliminary until published in a peer-reviewed medical journal.

More information: The U.S. National Heart, Lung, and Blood Institute has more about heart surgery.

Why does maximum heart rate drop with age?

Researchers at the University of Colorado have new insight into the age-old question of why maximum heart rate (maxHR) decreases with age. This decrease in maxHR not only limits the performance of aging athletes but it is also a leading cause for nursing home admittance for otherwise-healthy elderly individuals who no longer have the physical capacity required for independent living. We say we're just getting old and slowing down, but exactly what is it that is slowing down?

15 oct 2013--Everybody knows that aerobic capacity decreases with age. You know that chart in your gym that shows your target heart rate decreasing as you get older? Well, that's not a senior discount to let the elderly get off easy on their treadmill workouts. It's because older hearts simply can't beat as fast as younger hearts. So the older person who's doing 120 beats per minute is probably working harder—at a higher percentage of maximum heart rate—than the younger person who is at 150 beats per minute.

A new study by a group led by Catherine Proenza, PhD and Roger Bannister, PhD from the University of Colorado School of Medicine reports that one of the reasons for the age-dependent reduction in maximum heart rate is that aging depresses the spontaneous electrical activity of the heart's natural pacemaker, the sinoatrial node.

A dissertation from Eric D. Larson, a graduate from Proenza's lab in the Department of Physiology and Biophysics, is described in the article. Larson said, "I utilized a method to record ECGs from conscious mice and found that maximum heart rate was slower in older mice, just as it is in older people. This result wasn't unexpected. But what was completely new was that the slower maxHR was because the individual pacemaker cells—called sinoatrial myocytes, or 'SAMs'—from old mice just couldn't beat as fast as SAMs from young mice."

The researchers recorded the tiny electrical signals from the isolated cells and found that SAMs from old mice beat more slowly, even when they were fully stimulated by the fight-or-flight response which can be observed in these individual cells. The slower beating rate was due to a limited set of changes in the action potential waveform, the electrical signal that is generated by the cells. The changes were caused by altered behavior of some ion channels in the membranes of the older cells. (Ion channels are proteins that conduct electricity across the cell membrane. Imagine a balloon with little tiny pinholes that open and close to let the air in and out; ion channels are like the pinholes.)

Like most initial discoveries in basic science, this study opens many more questions and avenues for further research. But the significance of the study is that it raises the possibility that sinoatrial ion channels and the signaling molecules that regulate them could be novel targets for drugs to slow the loss of aerobic capacity with age. In the meanwhile, Proenza notes that "although maximum heart rate goes down for everybody equally, regardless of physical conditioning, people can improve and maintain their aerobic capacity at all ages by exercising."

This study will be published in the Oct. 14 Proceedings of the National Academy of Sciences.

More information: Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate, www.pnas.org/cgi/doi/10.1073/pnas.1308477110

Provided by University of Colorado Denver

Meta-analysis indicates widespread use of vitamin D supplements to prevent osteoporosis in healthy adults unjustified

Taking vitamin D supplements does not improve bone mineral density at the total hip, spine, forearm, or in the body as a whole, a large meta-analysis involving more than 4,000 healthy adults published in The Lancet has found. With close to half of adults aged 50 and older using vitamin D supplements, the authors conclude that continuing widespread use of these supplements to prevent osteoporosis in healthy adults is needless.

14 oct 2013--"Most healthy adults do not need vitamin D supplements", explains study leader Professor Ian Reid from the University of Auckland in New Zealand. "Our data suggest that the targeting of low-dose vitamin D supplements only to individuals who are likely to be deficient could free up substantial resources that could be better used elsewhere in healthcare."

Reid and colleagues from the University of Auckland conducted a systematic review and meta-analysis of all randomised trials examining the effects of vitamin D supplementation on bone mineral density in healthy adults up to July 2012.

Analysis of data from 23 studies involving 4082 healthy adults (average age 59 years) did not identify any effects for people who took vitamin D for an average period of 2 years, apart from a small but statistically significant increase in bone density (0.8%) at the femoral neck. According to the authors, such a localised effect is unlikely to be clinically significant.

The authors conclude, "This systematic review provides very little evidence of an overall benefit of vitamin D supplementation on bone density…Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems to be inappropriate."

Writing in a linked Comment, Clifford J Rosen from the Maine Medical Research Institute in the USA discusses how our recent understanding of vitamin D lends support to these findings, confirming that, "Supplementation to prevent osteoporosis in healthy adults is not warranted. However, maintenance of vitamin D stores in the elderly combined with sufficient dietary calcium intake (800–1200 mg per day) remains an effective approach for prevention of hip fractures."

More information: www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61647-5/abstract

Provided by Lancet

Psychological interventions halve deaths and CV events in heart disease patients

Psychological interventions halve deaths and cardiovascular events in heart disease patients, according to research from Athens, Greece, presented at the Acute Cardiac Care Congress 2013.

13 oct 2013--The Acute Cardiac Care Congress 2013 is the annual meeting of the Acute Cardiovascular Care Association (ACCA) of the European Society of Cardiology (ESC). It takes place 12-14 October in Madrid, Spain.

Dr Zoi Aggelopoulou, a nurse and one of the study authors, said: "The nurses on our coronary care unit observed that patients were less likely to have another heart attack, die, or return to hospital when we talked to them about their treatment, played music for them or helped religious patients to say prayers. It made us think that coronary heart disease is not just physical but also has a psychological component."

She added: "We wanted to find out if others had observed the same thing, and whether psychological support had a real impact on the outcomes of patients with coronary heart disease."

The current study was a meta-analysis of 9 randomised controlled trials. The researchers evaluated whether psychological interventions could improve outcomes of patients with coronary heart disease when combined with a conventional rehabilitation programme.

The researchers found that the addition of psychological interventions reduced mortality and cardiovascular events by 55% after 2 years or more.

Dr Aggelopoulou said: "We found a huge benefit of psychological interventions after 2 years, with less patients dying or having a cardiovascular event and therefore fewer repeat hospital visits. The interventions included talking to patients and their families about issues that were worrying them, relaxation exercise, music therapy, and helping them to say prayers."

She added: "Patients want to know what will happen to them when they leave hospital, whether or not they can have sex, and how to take their medication. Our research shows that giving them information and providing reassurance decreases the chances of them dying or having another heart attack. Patients can help instigate this new culture of information by asking more questions and getting more involved in decisions about their treatment."

Population-based studies have shown that psychological factors may have an influence on the likelihood of having a heart attack in the first place. The factors include depression, social isolation, low socioeconomic status, and chronic stress such as occupational or marital distress and stress from caregiving.

Dr Aggelopoulou said: "The results of our study strengthen the evidence that psychological factors have a big role to play in heart disease. Not only do they impact on the risk of having a heart attack, but they also affect the future outlook of a patient who has had a cardiovascular event. This validates our view that cardiovascular disease is not just a physical disease but also has a substantial psychological component."

The researchers concluded that psychological interventions should be incorporated into the rehabilitation of patients with coronary heart disease. Dr Aggelopoulou said: "More clinical trials are needed to clarify which interventions are most effective and how they can best be implemented."

She concluded: "We can help our patients by simply talking to them or introducing new things like music therapy into our clinical practice. Coronary units are busy places – in Greece we sometimes have 1-2 nurses for 10-20 patients in the coronary care unit and we are under time pressure. But our finding that the addition of psychological support on top of physiological therapies reduces death and cardiovascular events by 55% should be a wake-up call that these interventions really do work. Preventing repeat hospital visits would free up the time we need to implement them."

Provided by European Society of Cardiolog

New research suggests that high dietary intake of polyphenols are associated with longevity

It is the first time that a scientific study associates high polyphenols intake with a 30% reduction in mortality in older adults. The research, published on Journal of Nutrition, is the first to evaluate the total dietary polyphenol intake by using a nutritional biomarker and not only a food frequency questionnaire.

Polyphenols: diet improves health

12 oct 2013--Polyphenols are naturally occurring compounds found largely in fruits, vegetables, coffee, tea, nuts, legumes and cereals. More than 8,000 different phenolic compounds have been identified in plants. Polyphenols have antioxidant, antiinflammatory, anticarcinogenic, etc. effects.

The research published on Journal of Nutrition is based on a 12-year follow-up of a population sample composed by 807 men and women aged 65 or over from Greve and Bagno (Tuscany, Italy), within the InCHIANTI study. The group of the UB analysed the effect of polyphenol-rich diets by means of a nutritional biomarker —the total urinary polyphenol (TUP) concentration— as a proxy measure of intake. To be exact, UB researchers contributes to first literature references on TUP application to epidemiological or clinical studies.

New biomarkers for nutritional studies

Professor Cristina Andrés Lacueva, head of the Biomarkers and Nutritional & Food Metabolomics Research Group of the UB and coordinator of the study, explains that "the development and use of nutritional biomarkers enables to make a more precise and, particularly, more objective estimation of intake as it is not only based on participants' memory when answering questionnaire. Nutritional biomarkers take into account bioavailabity and individual differences. According to the expert, "this methodology makes a more reliable and accurate evaluation of the association between food intake and mortality or disease risk".

In conclusion, the research proves that overall mortality was reduced by 30% in participants who had rich-polyphenol diets (>650 mg/day) in comparison with the participants who had low-polyphenol intakes (<500 day="" mg="" p="">

Raúl Zamora Ros, first author of the study, points out that "results corroborate scientific evidence suggesting that people consuming diets rich in fruit and vegetables are at lower risk of several chronic diseases and overall mortality". Moreover, the research stresses the importance of evaluating —if possible— food intake by using nutritional biomarkers, not only food frequency questionnaires.

The Biomarkers and Nutritional & Food Metabolomics Research Group, which participates in the project Fun-C-Food (Consolider Ingenion), collaborates actively with several national and international research groups. It focuses its activity on the analysis of new more effective and sensitive nutritional biomarkers based on the bioavailabilty of bioactive compounds in food and their activity, in order to associate the intake of certain foods (consumption markers) with their potential effects on people's health.

More information: Zamora, R. et al. High concentrations of a urinary biomarker of polyphenol intake are associated with decreased mortality in older adults, Journal of Nutrition, June 2013. PMID: 23803472

Provided by University of Barcelona

Lab mice breakthrough offers Alzheimer's hope

Scientists say they have developed a drug which could be used to treat Alzheimer's, Parkinson's and other brain disorders

Scientists on Thursday said they had tested a drug that in mice prevented the death of brain cells, boosting hopes in the fight against Alzheimer's, Parkinson's and other neurodegenerative diseases.

11 oct 2013--Still at a very early and experimental stage, the drug blocks disruption of a defence system in the brain which plays a common role in these tragic disorders.

Many brain diseases start with the buildup of rogue, scrunched-up proteins, or amyloids.

The organ's response to this is to switch on a defence mechanism called the unfolded protein response, or UPR.

The mechanism orders cells to stop producing new proteins so that the problem is not worsened.

But the buildup of misshapen proteins prevents the UPR mechanism from being switched off.

As a result, the misshapen proteins are no longer made—but nor are normal proteins that are essential for brain-cell survival. Neurons start to die, are not replenished, and the disease progresses.

British researchers, reporting in the US journal Science Translational Medicine, tested a drug that works on a key point in this switching pathway, an enzyme called PERK, to keep protein production open.

Known by its lab name as GSK2606414—it is made by British drugmaker GlaxoSmithKline—the orally-administered drug was tested on 29 mice with prion disease, a family of disorders that includes Creuzfeldt-Jakob disease.

These were compared against a group of "control" mice, whose brain had also been infected with prions but which did not receive the drug.

Mice that were treated seven weeks after being infected with the prions suffered no memory loss in a test to recognise a familiar object, but those treated at nine weeks lost their memory.

The mice were killed and autopsied, and examination of samples under a microscope confirmed that brain-cell death among all the treated mice was very low, although less so among the nine-week group.

The University of Leicester team say they are hugely buoyed by the success, although many more years of tests lie ahead.

"We were extremely excited when we saw the treatment stop the disease in its tracks and protect brain cells, restoring some normal behaviours and preventing memory loss in the mice," said Giovanna Mallucci, a professor of toxicology.

"We're still a long way from a usable drug for humans - this compound had serious side effects," Mallucci told Britain's Press Association.

"But the fact we have established that this pathway can be manipulated to protect against brain cell loss, first with genetic tools and now with a compound, means that developing drug treatments targeting this pathway for prion and other neurodegenerative diseases is now a real possibility."

If the drug eventually progressed to human patients, people would need treatment "for years or even decades in many cases," the study also cautioned.

In a commentary carried in the same journal, neuroscientists Wiep Scheper and Jeroen Hoozemans of the Free University of Amsterdam said the research may have thrown open "a new therapeutic strategy."

They too were prudent.

They said mouse models designed to replicate human brain disease had limitations, and in humans, loss of the PERK enzyme also had side-effects in promoting diabetes and skeletal defects.

Eric Karran, director of research at the British charity Alzheimer's Research UK, said the idea of a single drug to target a mechanism shared by a range of diseases was compelling.

"But this compound is still at an early stage. It will be important for these findings to be repeated and tested in models of other neurodegenerative diseases, including Alzheimer's disease," he said in a statement.

"(...) What is true in animals does not always hold true in people and the ultimate test for this compound will be to see whether it is safe and effective in people with these diseases."

Alzheimer's is the commonest form of dementia, a condition that afflicts nearly 35.6 million people around the globe, according to the World Health Organisation (WHO).

This number is expected to reach 65.7 million by 2030 and 115.4 million by 2050.

Treating and caring for people with dementia currently costs the world more than $600 billion (440 billion euros) per year, the WHO says.

More information: "An Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice," by J.A. Moreno et al. Science Translational Medicine, 2013.

"A New PERKspective on Neurodegeneration," by W. Scheper et al. Science Translational Medicine, 2013.

New study links depression in newly diagnosed Parkinson's disease patients to reduced striatal dopamine synthesis

According to the Parkinson's Disease Foundation, up to 60% of individuals with Parkinson's disease (PD) exhibit mild to moderate depression, which is often underdiagnosed. It is unclear whether depression results from having a debilitating disease or reflects a parallel abnormal change in the brain caused by PD pathophysiology.

10 oct 2013--One hypothesis is that depression in PD may reflect impaired striatal dopamine function, but previous investigations have produced contradictory results. By scanning the brains of newly diagnosed patients not yet taking PD medications, Finnish investigators have shown that the level of depression is inversely related to the ability to synthesize dopamine in the striatum and the effect is seen only in the left striatum. Their results are published in the latest issue of the Journal of Parkinson's Disease.

Depression in Parkinson's patients can reduce quality of life and impede daily activities, and those with depressive symptoms tend to begin medications for motor symptoms earlier than those who are not depressed. Treating depression can improve both quality of life and movement, and medications such as dopamine agonists have antidepressant effects in PD patients.

In the current report, investigators used 18fluorodopa PET scans to look at two different groups of PD patients. One group consisted of 15 de novo patients, meaning that the patients were newly diagnosed with PD and that they had never been treated with PD medications such as levodopa. The average PD disease duration for this group was less than 5 years. Two of these patients were diagnosed with clinical depression.

In the unmedicated PD group, the authors found significant negative correlations between symptoms of depression (as measured by the Beck Depression Inventory (BDI)) and dopamine synthesis capacity (as measured by FDOPA uptake) in the left striatum (putamen p=0.002, caudate p=0.042). No significant correlations were observed in the right striatum. Neither the severity nor side of motor symptoms affected the findings.

Different results were found in a group of 20 patients with moderate disease severity who were already being treated with PD medications. The average duration of disease for these patients was 5.6 years and 90% were using levodopa, 90% a dopamine agonist, and 60% a MAO-B inhibitor. Ten percent were also on an antidepressant. In this group, no significant correlations were found between BDI scores and regional FDOPA uptake in the caudate or putamen.

"Previous studies looking at depression and striatal dopamine synthesis capacity using 18Ffluorodopa PET scanning yielded inconsistent results, most likely reflecting marked heterogeneity in patients' disease severity and medication history," says lead investigator Juho Joutsa, MD, of the Division of Clinical Neurosciences at Turku University Hospital and University of Turku in Finland. "The results should be interpreted to indicate a link between mood and dopamine, which can be observed in early-stage unmedicated patients, but the relationship may also be present, but masked, in more advanced patients."

The study was the first using 18fluorodopa PET scanning technology to show that depression was associated with reduced dopamine synthesis capacity only on the left side. However, Dr. Joutsa comments that studies using dopamine transporter ligands have also reported a similar lateralization of effect.

PD is the second most common neurodegenerative disorder in the United States, affecting approximately one million Americans and five million people worldwide. Its prevalence is projected to double by 2030. The most obvious symptoms are movement-related, such as involuntary shaking and muscle stiffness. Non-motor symptoms, such as worsening depression, anxiety, and sleep disturbances, can appear prior to the onset of motor symptoms.

More information: Joutsa, J. et al. Reduced Striatal Dopamine Synthesis Capacity is Associated with Symptoms of Depression in Patients with de novo Unmedicated Parkinson's Disease, Journal of Parkinson's Disease, Volume 3/Issue 3. DOI: 10.3233/JPD-130205

Provided by IOS Press