Alzheimer's linked to unsaturated fatty acids in the brain

While it is not yet clear what causes Alzheimer's disease, researchers are examining a variety of genetic, environmental, and lifestyle causes. New research examines some of the key brain regions involved in the development of Alzheimer's and finds several fatty acids to be associated with this form of dementia.

New research examines the levels of fatty acids in brain regions vulnerable to Alzheimer's disease.

The Alzheimer's Association estimate that every 66 seconds, an adult in the United States develops Alzheimer's disease (AD). Alzheimer's-related mortality has increased by as much as 89 percent since the year 2000.

Researchers are hard at work trying to understand what causes AD. It is estimated that the disease affects 1 in 3 older adults in the U.S., and understanding why Alzheimer's tends to strike seniors, in particular, is at the heart of the medical community's research efforts.

Researchers are studying late-onset Alzheimer's in the context of age-related brain changes. A new study - published in the journal PLOS Medicine - looks at how fatty acid metabolites in the brain tissue of healthy seniors behave and affect the participants' cognitive abilities.

The international research team - led by Cristina Legido-Quigley of King's College London in the United Kingdom, and Madhav Thambisetty of the National Institute on Aging in the U.S. - conducted a nontargeted metabolite profiling study that analyzed the concentration of 100 different fatty acid metabolites in the brain tissues of seniors who participated in the Baltimore Longitudinal Study of Aging.

The participants were assessed cognitively in the year prior to their deaths, and their brain tissue was tested for neuropathologies during autopsy.

Legido-Quigley and her colleagues divided the participants into three groups: 14 participants had healthy brains, 15 had a neuropathological buildup of the tau protein or a buildup of amyloid plaque, but no memory problems, and a final group of 14 participants had AD.

Amyloid plaques and tau tangles are abnormal clusters of protein and bundles of fiber, respectively, which are considered to be the main features of AD.

Six unsaturated fatty acids linked to AD

The researchers measured the metabolite levels of the brain regions commonly associated with Alzheimer's: the middle frontal gyrus and the inferior temporal gyrus. They also examined metabolite levels in a brain area that is not normally affected by Alzheimer's pathology - the cerebellum.

The study revealed that six unsaturated fatty acids (UFAs) found in the middle frontal and inferior temporal gyri correlated with AD.

Fatty acids are essential nutrients that provide the human body with energy. Fats are made of fatty acids, which can be saturated or unsaturated. Dietary saturated fats can raise the levels of the "bad" type of cholesterol - namely, the low-density lipoprotein cholesterol - while unsaturated ones can lower it.

The fatty acids shown to correlate with AD in this study were: docosahexaenoic acid, linoleic acid, arachidonic acid, linolenic acid, eicosapentaenoic acid, and oleic acid.

Cristina Legido-Quigley and colleagues explain the significance of the study:

"[This] work suggests that dysregulation of UFA's metabolism plays a role in driving AD pathology and that these results provide further evidence for the metabolic basis of AD pathogenesis."

The authors also concede some of the study's limitations. Due to its observational nature, the research cannot explain causality, so it could not be established whether the UFA dysregulation causes AD or whether it is the other way around.

Additionally, the authors note that larger studies are needed to replicate and confirm the findings. Their study sample was small, as there are not many studies available that examined tissue samples together with cognitive evaluations. Furthermore, the nature of nontargeted metabolomic studies is quite limited, as not all metabolites can be identified at once, so further studies are needed to locate other metabolites.

Learn how scientists stopped and reversed Alzheimer's-related brain damage in mice.

Written by Ana Sandoiu

Drinking tea could help stave off cognitive decline

Thanks to its high levels of antioxidants, tea has been linked to a lower risk of diabetes, heart disease, and cancer. However, its potential health benefits may not end there. Researchers have found that regular tea consumption could more than halve the risk of cognitive decline for older adults, particularly for those with a genetic risk of Alzheimer's disease.

New research suggests that regular tea intake could lower the risk of cognitive decline in later life.

Tea is one of the most popular beverages in the United States; in 2015, more than 3.6 billion gallons of tea were consumed in the country, with black tea being the favorite.

The possible health benefits of tea consumption have been well documented. A recent study published in The American Journal of Public Health, for example, associated moderate tea intake with a reduced risk of cardiovascular events.

Past research has suggested that drinking tea may also have brain benefits, with one study linking green tea consumption to better working memory.

For this latest study, lead investigator Feng Lei, from the Department of Psychological Medicine at National University of Singapore's (NUS) Yong Loo Lin School of Medicine, and colleagues sought to determine whether there might be a link between tea intake and cognitive decline.

The researchers came to their findings - published in The Journal of Nutrition, Health & Aging - by collecting data from 957 Chinese adults aged 55 and older.

Between 2003 and 2005, the team collected information on the participants' tea consumption, including how much tea they drink, frequency of tea consumption, and what types of tea they consume.

Every 2 years until 2010, the participants underwent standardized assessments that evaluated their cognitive function.

The researchers identified 72 new cases of neurocognitive disorders among participants between 2006 and 2010.

Up to 86 percent lower risk of cognitive decline for tea drinkers

Compared with adults who rarely drank tea, those who consumed tea regularly were found to have a 50 percent lower risk of cognitive decline.

Furthermore, among adults who possessed the APOE e4 gene - which is associated with an increased risk of Alzheimer's disease - those who drank tea regularly were found to be at 86 percent lower risk of cognitive decline.

These findings remained after accounting for numerous confounding factors, including the presence of other medical conditions, social activity, physical activity, and other lifestyle factors.

The researchers note that the cognitive benefits were seen with consumption of tea that was brewed from tea leaves, such as green tea, black tea, and oolong tea.

The study was not designed to pinpoint the mechanisms behind tea's potential brain benefits, but Lei says that it could be down to the beneficial compounds the beverage contains, such as theaflavins, catechins, thearubigins, and L-theanine.

"These compounds exhibit anti-inflammatory and antioxidant potential and other bioactive properties that may protect the brain from vascular damage and neurodegeneration," Lei explains. "Our understanding of the detailed biological mechanisms is still very limited so we do need more research to find out definitive answers."

A 'simple, inexpensive lifestyle measure' could prevent dementia

According to the World Health Organization (WHO), around 47.5 million people worldwide are living with dementia, and there are around 7.7 million new cases of the condition every year.

By 2050, it is estimated that the number of people living with dementia will have risen to 135.5 million.

Although the study from Lei and team was conducted in Chinese adults, the researchers say that their findings are likely to apply to other populations, and they could have important implications for the prevention of dementia.

"Despite high-quality drug trials, effective pharmacological therapy for neurocognitive disorders such as dementia remains elusive and current prevention strategies are far from satisfactory.

Tea is one of the most widely consumed beverages in the world. The data from our study suggests that a simple and inexpensive lifestyle measure such as daily tea drinking can reduce a person's risk of developing neurocognitive disorders in late life."

Feng Lei

The researchers plan to conduct further studies on the link between tea and cognitive function. In particular, they want to carry out randomized controlled trials to rigorously test the health effects of tea's bioactive compounds.

Learn how a compound in green tea could help to treat Down syndrome.

Written by Honor Whiteman

Psychiatric disorders do not increase risk of Alzheimer 's disease

Psychiatric disorders do not increase the risk of Alzheimer's disease, according to a recent study from the University of Eastern Finland. However, the prevalence of psychiatric diagnoses increased before the Alzheimer's diagnosis, which might be due to prodromal symptoms of Alzheimer's disease. The results were published in European Psychiatry.

History of mood disorder, such as depression, or any psychiatric disorder were associated with a higher risk of Alzheimer's disease when psychiatric disorders that occurred at least five years before the Alzheimer's diagnosis were taken into account. However, the associations disappeared when this time window was extended to 10 years. The exponential increase in the prevalence of psychiatric disorders before the diagnosis implies that some of these psychiatric disorders might actually have been prodromal symptoms of Alzheimer's disease. This underlines the importance of proper differential diagnostics of Alzheimer's disease. Further, the findings also highlight the importance of using an appropriate time window when assessing the risk factors of neurodegenerative diseases with a long onset period. Otherwise the identified "risk factors" may actually be manifestations of the neurodegenerative disease.

It should also be acknowledged that although psychiatric disorders diagnosed 10-40 years before Alzheimer's disease were not related to a higher risk, the life expectancy of persons with psychiatric disorders was, and is still decreased. Thus, those persons with psychiatric disorders who lived long enough to develop Alzheimer's disease were a selected sample of all persons with psychiatric disorders.

The study was conducted in the MEDALZ-2005 cohort which included all Finnish community dwellers with clinically verified Alzheimer's disease at the end of 2005 and their age, sex and region of residence matched controls (N of case-control pairs 27,948). History of psychiatric disorders since 1972 was extracted from the Finnish Hospital Discharge Register. Chronic disorders and substance abuse were taken into account.

Article: Hospital-treated mental and behavioral disorders and risk of Alzheimer's disease: A nationwide nested case-control study, V. Tapiainen, S. Hartikainen, H. Taipale, J. Tiihonen, A.-M. Tolppanen, European Psychiatry, doi: 10.1016/j.eurpsy.2017.02.486, published online March 2017.

SuperAger brains shrink more slowly than peers' brains

Cortex of super-aged brain deteriorated much slower than average elderly brain over time.

Donald Tenbrunsel is 89 years old, but he is just as likely to talk to you about Chance the Rapper as reminisce about Frank Sinatra.

The highly engaged and delightful conversationalist, who reads, volunteers and routinely researches questions on the Internet, is part of a new path-breaking Northwestern Medicine study that shows that SuperAgers' brains shrink much slower than their age-matched peers, resulting in a greater resistance to "typical" memory loss and dementia.

Over the course of the 18-month study, normal agers lost volume in the cortex twice as fast as SuperAgers, a rare group of people aged 80 and above whose memories are as sharp as those of healthy persons decades younger.

"Increasing age is often accompanied by 'typical' cognitive decline or, in some cases, more severe cognitive decline called dementia," said first author Amanda Cook, a clinical neuropsychology doctoral student in the laboratory of Emily Rogalski and Sandra Weintraub. "SuperAgers suggest that age-related cognitive decline is not inevitable."

The study was published in JAMA. Senior author Emily Rogalski will present the findings at the 2017 Cognitive Aging Summit in Bethesda, Maryland, April 6.

SuperAger Tenbrunsel, who lives with his daughter's family, is intent on being a good conversationalist with his three grandchildren.

"I have to adapt to that kind of life," Tenbrunsel said. "They don't know much about Frank Sinatra or Franklin Delano Roosevelt, so I have to keep saying, 'Is the Chance the Rapper coming this week or is it Taylor Swift?'"

The researchers already knew SuperAgers' brains tended to retain more brain volume and typically don't show the same wear-and-tear as normal agers.

"For this study we explored whether SuperAgers' brains were on a different trajectory of decline," said Rogalski, associate professor at the Cognitive Neurology and Alzheimer's Disease Center (CNADC) at Northwestern University Feinberg School of Medicine. "We found that SuperAgers are resistant to the normal rate of decline that we see in average elderly, and they're managing to strike a balance between life span and health span, really living well and enjoying their later years of life."

Using magnetic resonance imaging (MRI), the scientists measured the thickness of the cortex in 24 SuperAgers and 12 same-age, educationally and cognitive average peers (control group) to determine the approximate health of the brain over 18 months. The annual percent decline in thickness between the first and second visit for the SuperAgers was 1.06 and 2.24 for the control group.

Previous research showed that SuperAgers have a thicker cortex than those who age normally. By studying what makes SuperAgers unique, the scientists said they hope to undercover biological factors, such as the reduced cortical brain atrophy demonstrated here, that might contribute to the maintenance of memory ability in advanced age.

SuperAger research at Northwestern is flipping the traditional approach to Alzheimer's research of focusing on brains that are underperforming to instead focusing on outperforming brains.

"Sometimes it's useful to turn a complex problem on its head and look from a different vantage point," Rogalski said. "The SuperAging program studies people at the opposite end of the spectrum: those with unexpectedly high memory performance for their age."

Other Northwestern authors on the study include Jaiashre Sridhar, Daniel Ohm, Alfred Rademaker, Dr. M. Marsel Mesulam and Sandra Weintraub.

The research was funded by grants from the National Institutes of Health, including R01AG045571 and P30 AG13854 from the National Institute on Aging, T32 NS047987 from the National Institute of Neurological Disorders and Stroke, as well as the Davee Foundation.

Article: Rates of Cortical Atrophy in Adults 80 Years and Older With Superior vs Average Episodic Memory, Amanda H. Cook, MA; Jaiashre Sridhar, MS; Daniel Ohm, BS; Alfred Rademaker, PhD; M.-Marsel Mesulam, MD; Sandra Weintraub, PhD; Emily Rogalski, PhD, JAMA, doi: 10.1001/jama.2017.0627, published 4 April 2017.

Neurological diseases cost the U.S. nearly $800 billion per year

A new paper published in the Annals of Neurology reports the most common neurological diseases pose a serious annual financial burden for the nation.

The report notes that the current estimated annual cost to American society of just nine of the most common neurological diseases is staggering, totaling $789 billion in 2014 dollars. These conditions include Alzheimer's disease and other dementias, low back pain, stroke, traumatic brain injury, migraine, epilepsy, multiple sclerosis, spinal cord injury, and Parkinson's disease.

Costs will increase even further over the coming years as the elderly segment of the population nearly doubles between 2011 and 2050. The costs of dementia and stroke alone are projected to total over $600 billion by 2030. The article provides an action plan for reducing this burden through infrastructure investment in neurological research and enhanced clinical management of neurological disorders.

"The findings of this report are a wake-up call for the nation, as we are facing an already incredible financial burden that is going to rapidly worsen in the coming years," said lead author Dr. Clifton Gooch. "Although society continues to reap the benefits of the dramatic research investments in heart disease and cancer over the last few decades, similar levels of investment are required to fund neuroscience research focused on curing devastating neurological diseases such as stroke and Alzheimer's, both to help our patients and also to avoid costs so large they could destabilize the entire health care system and the national economy."

Article: The Burden of Neurological Disease in the United States: A Summary Report and Call to Action, Clifton L. Gooch MD, Etienne Pracht PhD and Amy R. Borenstein, PhD, Annals of Neurology, doi: 10.1002/ana.24897, published online 15 February 2017.

Detecting Alzheimer's disease earlier using ... Greebles?

Difficulty distinguishing novel objects is associated with family history of Alzheimer's disease.

Unique graphic characters called Greebles may prove to be valuable tools in detecting signs of Alzheimer's disease decades before symptoms become apparent.

In an article published online in the Journal of Alzheimer's Disease, Emily Mason, Ph.D., a postdoctoral associate in the Department of Neurological Surgery at the University of Louisville, reported research showing that cognitively normal people who have a genetic predisposition for Alzheimer's disease (AD) have more difficulty distinguishing among novel figures called Greebles than individuals without genetic predisposition.

Alzheimer's disease (AD) is a progressive, irreversible neurodegenerative disease characterized by declining memory, cognition and behavior. AD is the most prevalent form of dementia, affecting an estimated 5.5 million individuals in the United States and accounting for 60 to 80 percent of dementia cases. The ability to detect the disease earlier may allow researchers to develop treatments to combat the disease.

"Right now, by the time we can detect the disease, it would be very difficult to restore function because so much damage has been done to the brain," Mason said. "We want to be able to look at really early, really subtle changes that are going on in the brain. One way we can do that is with cognitive testing that is directed at a very specific area of the brain."

AD is characterized by the presence of beta amyloid plaques and tau neurofibrillary tangles in the brain. Tau tangles predictably develop first in the perirhinal and entorhinal cortices of the brain, areas that play a role in visual recognition and memory. Mason and her colleagues developed cognitive tests designed to detect subtle deficiencies in these cognitive functions. They hoped to determine whether changes in these functions would indicate the presence of tau tangles before they could be detected through imaging or general cognitive testing.

Working in her previous position at Vanderbilt University, Mason identified test subjects age 40-60 who were considered at-risk for AD due to having at least one biological parent diagnosed with the disease. She also tested a control group of individuals in the same age range whose immediate family history did not include AD.

The subjects completed a series of "odd-man-out" tasks in which they were shown sets of four images depicting real-world objects, human faces, scenes and Greebles in which one image was slightly different than the other three. The subjects were asked to identify the image that was different.

The at-risk and control groups performed at similar levels for the objects, faces and scenes. For the Greebles, however, the at-risk group scored lower in their ability to identify differences in the images. Individuals in the at-risk group correctly identified the distinct Greeble 78 percent of the time, whereas the control group correctly identified the odd Greeble 87 percent of the time.

"Most people have never seen a Greeble and Greebles are highly similar, so they are by far the toughest objects to differentiate," Mason said. "What we found is that using this task, we were able to find a significant difference between the at-risk group and the control group. Both groups did get better with practice, but the at-risk group lagged behind the control group throughout the process."

Which Greeble is different?
Image Credit: Greeble images courtesy of Michael J. Tarr, Center for the Neural Basis of Cognition and Department of Psychology, Carnegie Mellon University

Mason would like to see further research to determine whether the individuals who performed poorly on the test actually developed AD in the future.

"The best thing we could do is have people take this test in their 40s and 50s, and track them for the next 10 or 20 years to see who eventually develops the disease and who doesn't," Mason said.

In recent years, a great deal of research has focused on identifying early biomarkers of Alzheimer's disease. However, not everyone who has an individual biomarker ultimately develops the disease. Brandon Ally, Ph.D., assistant professor of neurological surgery at UofL and senior author of the publication, said the tests with Greebles can provide a cost-effective way to identify individuals who may be in the early stages of AD, as well as a tool for following those individuals over time.

"We are not proposing that the identification of novel objects such as Greebles is a definitive marker of the disease, but when paired with some of the novel biomarkers and a solid clinical history, it may improve our diagnostic acumen in early high-risk individuals," Ally said. "As prevention methods, vaccines or disease modifying drugs become available, markers like novel object detection may help to identify the high priority candidates."

Robert P. Friedland, M.D., professor and Mason and Mary Rudd Endowed Chair in Neurology at UofL, has studied clinical and biological issues in Alzheimer's disease and related disorders for 35 years. He believes that early detection will enhance the ability of patients and physicians to employ lifestyle and therapeutic interventions.

"This work shows that the effects of Alzheimer's disease on cognition can be measured decades before the onset of dementia," Friedland said. "The fact that the disease takes so long to develop provides us with an opportunity to slow its progression through attention to the many factors that are linked to the disease, such as a sedentary lifestyle, a high fat diet, obesity, head injury, smoking, and a lack of mental and social engagement."

Article: Family History of Alzheimer's Disease is Associated with Impaired Perceptual Discrimination of Novel Objects, Journal of Alzheimer's Disease, doi: 10.3233/JAD-160772, published 10 April 2017.

ANSWER: Greeble No. 4 is different.

Dementia not prevented with vitamin E, selenium, study finds

An ample body of research has shown that oxidative stress plays a key role in the development of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. As a result, antioxidant supplements have been proposed as preventive measures against dementia. A new trial, however, tests the effect of vitamin E and selenium on aging men and finds no evidence that they have therapeutic value.

New research investigates the effects of antioxidant supplements on dementia and does not recommend vitamin E or selenium as preventive agents.

In neurodegenerative disorders such as Alzheimer's disease or Parkinson's disease, brain cells die slowly but irreversibly. While researchers do not know exactly what causes dementia and other neurodegenerative conditions, the process of oxidative stress has been shown to play a key role.

Oxidative stress is a process commonly associated with advancing age. It is a form of physiological damage on the body caused by an accumulation of free radicals.

A healthy body normally maintains a balance between free radicals and antioxidants, but when free radicals are found in overwhelming numbers, our body's lipids, proteins, and DNA are damaged, thus causing a number of diseases.

Therefore, some studies have suggested that an intake of antioxidants from dietary supplements may help to restore the body's antioxidant/free radicals balance, with a specific focus on the benefits of antioxidants on cognitive impairment.

Vitamin E and selenium have both been shown to have antioxidant properties. A new study - by Richard J. Kryscio, Ph.D., of the University of Kentucky in Lexington, and his colleagues - presents the results of a clinical trial that examined the ability of these two supplements to ward off dementia in asymptomatic older men.

The findings were published in JAMA Neurology.

Vitamin E and selenium 'not recommended as preventive agents'

The Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADViSE) is a double-blind, randomized clinical trial that began in May 2002.

PREADViSE was part of the Selenium and Vitamin E Cancer Prevention Trial (SELECT), designed to test the effects of vitamin E and selenium on prostate cancer.

SELECT closed in 2009, and the remaining PREADViSE trial turned into a cohort study running from September 2009 to May 2015.

The PREADViSE trial included 7,540 men aged 60 and above, 3,786 of whom carried on to participate in the cohort study. During the trial, the men were randomly assigned to receive vitamin E, selenium, a combination of the two, or a placebo.

Throughout the trial, as well as in the cohort study, the participants were assessed for dementia using a two-stage screen, and they were encouraged to see a physician for a checkup if the results suggested the possibility of cognitive impairment.

Finally, the scientists used Cox proportional hazards models to adjust for race, ethnicity, and other demographic information, as well as for the presence of comorbidities.

The study found that neither of the two supplements, either taken alone or in combination, prevented dementia.

The authors note that to their knowledge, this is the first study that examines the long-term effect of antioxidant supplements on dementia in asymptomatic men. Kryscio and colleagues also admit some of the study's limitations - for example, the fact that it lost half of its participants during the transition to a cohort study. Additionally, the researchers point out that the randomized trial and cohort study may have also been biased by the publicity around the adverse effects of supplements.

The authors conclude:

"The supplemental use of vitamin E and selenium did not forestall dementia and are not recommended as preventive agents. This conclusion is tempered by the underpowered study, inclusion of only men, a short supplement exposure time, dosage considerations and methodologic limitations in relying on real-world reporting of incident cases."

Learn how hospital-induced delirium might speed up dementia.

Written by Ana Sandoiu

Novel link between unhealthy hearts and dementia

Researchers from National University Health System (NUHS) have discovered a link between cardiac diseases and brain dysfunction. The findings by a joint team of cardiovascular and brain researchers uncovered a strong association between cardiac diseases and tiny brain lesions called cerebral microinfarcts (CMIs) which are commonly found in patients with cognitive impairment or dementia.

The study is a collaboration between two research centres of NUHS, the Cardiovascular Research Institute (CVRI) and the Memory Ageing and Cognition Centre (MACC). The results were published in JAMA Neurology, a journal of the American Medical Association, and suggest that treating cardiac dysfunction could also help to prevent CMI-related brain injury. Previous studies have shown that the presence of CMIs is relatively uncommon in elderly individuals without dementia (24%), but more common in patients diagnosed with Alzheimer's disease (43%) or vascular dementia (62%).

"Our findings suggests that the development of these tiny brain lesions, which are closely linked to diseases like dementia, may be caused by chronic heart problems and vascular disease," said Associate Professor Christopher Chen, Director of MACC. CMIs were previously considered impossible to detect in living patients but the team had used higher field strength (3Tesla) magnetic resonance imaging (MRI) to identify CMIs in the brain of living persons. "In an earlier study, we showed these microinfarcts were associated with cognitive dysfunction, and now we show that they are also associated with clinical and subclinical cardiac disease," added lead author, Dr Saima Hilal, a visiting Research Fellow at the MACC and post-doctoral scientific researcher at the Erasmus Medical Center, Rotterdam, Netherlands.

The researchers studied a sample size of 243 elderly participants (average age 72 years). The presence of cortical CMIs was strongly associated not only with clinically overt cardiac disease but also with blood cardiac biomarkers. Repeat analysis after exclusion of individuals with clinically overt cardiac disease showed a correlation of the number of cortical CMIs with blood biomarkers of subclinical cardiac disease. A rise in cardiac markers was accompanied by an increased risk of developing CMIs.

"Apart from signalling problems with the heart, these cardiac biomarkers are also indicators of injury to circulatory and blood vessel systems in other organs, for example the brain. Our selected cardiac markers are powerful predictors of the presence of CMIs and cognitive impairment, and may provide scientists and clinicians with tools for the prevention or timely treatment of brain-related diseases," said Professor Arthur Mark Richards, Director of CVRI at NUHS' National University Heart Centre, Singapore (NUHCS), and Professor, Department of Medicine, National University of Singapore (NUS). Research teams at both CVRI and in Prof Richards' New Zealand laboratory have pioneered the use of cardiac biomarkers in detecting and monitoring heart disease, and in linking them to circulatory problems elsewhere in the body.

The success of the study leverages the cross-disciplinary research that exists in NUHS to advance cutting-edge translational biomedical research. The combination of close research collaboration between experts from different disciplines, such as the heart and brain, and access to advanced research tools like the 3Tesla MRI at the A*STAR-NUS Clinical Imaging Research Centre (CIRC) that was used in identifying CMIs, was instrumental in enabling this advance.

The researchers are looking to expand the study to gain a better understanding of the role that cardiac dysfunction plays in the development of CMIs, and if the findings are applicable to non-Asian populations who may have different risk profiles. Further studies may also determine if treatments for cerebrovascular disease-related cognitive impairment can be achieved by targeting cardiac disease.

Article: Association Between Subclinical Cardiac Biomarkers and Clinically Manifest Cardiac Diseases With Cortical Cerebral Microinfarcts, Saima Hilal, PhD; Yuek Ling Chai, BSc; Susanne van Veluw, PhD; et al., JAMA Neurology, doi: 10.1001/jamaneurol.2016.5335, published online 6 February 2017.

Advocates, Senators Call for More Alzheimer's Funding

WASHINGTON -- Physicians joined journalist Maria Shriver to advocate for funding and public attention to address Alzheimer's disease during a Senate Special Committee on Aging hearing Wednesday afternoon, urging senators to oppose the Trump Administration's proposed cuts to the National Institutes of Health budget, and calling for people to change daily habits and for a larger provider workforce to stave off a potential public health crisis.

Shriver is founder of the Women's Alzheimer's Movement. Her father, politician Sargent Shriver, died of Alzheimer's disease. She told the committee that the pace of research -- even with no federal cuts -- is "not fast enough." Instead of reductions, she urged Congress to increase funding by $414 million in fiscal 2018. "The statement 'we just don't know' needs to be repealed and replaced ... Without a federal commitment, we are going to lose this fight."

Kristine Yaffe, MD, a prominent neuropsychiatrist with the University of California San Francisco, followed Shriver to the microphone.

Speaking of brain research in the aging more broadly, Yaffe, who serves on the Alzheimer's Association's Medical and Scientific Advisory Committee, said, "This is critical that NIH fund this."

Recent research suggests the importance of cardiovascular health, including lowering hypertension and being physically active, Yaffe said; she recommended people follow guidelines beginning in their 20s to prevent the disease.

Alzheimer's presents a vital public health challenge, senators acknowledged, in part because of the large baby-boom generation. "Given our rapidly aging population, we cannot afford to do nothing," committee chair Sen. Susan Collins (R-Maine) said, calling for a public health approach to addressing brain health more broadly.

That approach should include more and enhanced caregiver training, and encouraging more people to become caregivers and specialize in treating Alzheimer's patients. The patient demand already exceeds the medical help available, Collins said, and projections say the gap will only widen without reform. Already the most expensive disease in the U.S., Alzheimer's prevalence is expected to triple by 2050 and associated costs to quadruple, Yaffe said.

Witnesses also noted that Alzheimer's affects a higher portion of women. It's especially problematic, said Shriver, because "most women don't know they're at risk" and even major diseases cancers and HIV/AIDS are treatable now, whereas Alzheimer's disease is not.

Shriver challenged everyone in the room to "give us the first person who survives a diagnosis of Alzheimer's disease." She added: "I envision a cure ... I don't mean 20 years from now, I mean five or 10 years."

In a statement submitted as part of her testimony, Yaffe said, "I believe that determining why women are more affected will help us unlock some of the mysteries of this disease."

Committee members promised to address that. Collins noted in February she co-authored a letter asking President Trump to increase Alzheimer's research funding in the budget and co-introduced a Senate resolution "declaring that that the goal of preventing and effectively treating Alzheimer's disease by 2025 is an 'urgent national priority.'"

However, Trump proposed a nearly 20% reduction in NIH funding in his 2018 budget request.

Sen. Bob Casey (D-Pa.) called the proposal "a giant step backwards," particularly in light of last year's bipartisan passage of the 21st Century Cures Act that included significant funding increases and other measures to enhance medical innovation.

"We will fight these cuts," said Sen. Richard Blumenthal (D-Conn.).

2017-03-30T18:00:00-0400

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Dementia: The right to rehabilitation

Rehabilitation is important for people with dementia as it is for people with physical disabilities, according to a leading dementia expert.

Linda Clare, Professor of Clinical Psychology of Aging and Dementia at the University of Exeter, said people with dementia have a right to cognitive rehabilitation - and it is as relevant for them as physical rehabilitation for people with physical impairments.

Writing in the journal PLOS Medicine, Professor Clare said both share a goal to enable people to participate in everyday life, and in their families and communities, in a way that is meaningful to them.

Professor Clare said: "We tend to think of rehabilitation in terms of people with physical impairment following an injury, but it is equally important in people with cognitive impairment. As a society, we now have a much greater recognition that people with physical disabilities have the right to access services and opportunities, but there it still a long way to go for people with "hidden" disabilities such as dementia, in a landscape where the numbers of people with dementia are expected to rise from 44 mill in 2015 to 117 million by 2050.

Professor Clare oversees the GREAT trial, which is assessing the success of cognitive rehabilitation in more than 500 people across eight sites in the UK. It focuses on tailor-made approaches to the specific, individual problems people encounter at different stages of dementia. Examples may include people wanting to use email to stay in contact with family and friends, gain confidence to go outside, or manage daily tasks better. For people in the more advanced stages of dementia, approaches may focus on being able to dress independently or engage in pleasurable activities.

Professor Clare believes the positive rehabilitation approach may be partially funded through redeploying some of the spend on dementia, through preventing physical difficulties, limiting the costs of managing distressing symptoms, and delaying institutionalisation. She stressed the need to develop service systems that train staff and involve families.

Article: Rehabilitation for people living with dementia: A practical framework of positive support, Linda Clare, PLOS Medicine, doi: 10.1371/journal.pmed.1002245, published 7 March 2017.

Insulin resistance may lead to faster cognitive decline

A new Tel Aviv University study published in the Journal of Alzheimer's Disease finds that insulin resistance, caused in part by obesity and physical inactivity, is also linked to a more rapid decline in cognitive performance. According to the research, both diabetic and non-diabetic subjects with insulin resistance experienced accelerated cognitive decline in executive function and memory.

The study was led jointly by Prof. David Tanne and Prof. Uri Goldbourt and conducted by Dr. Miri Lutski, all of TAU's Sackler School of Medicine.

"These are exciting findings because they may help to identify a group of individuals at increased risk of cognitive decline and dementia in older age," says Prof. Tanne. "We know that insulin resistance can be prevented and treated by lifestyle changes and certain insulin-sensitizing drugs. Exercising, maintaining a balanced and healthy diet, and watching your weight will help you prevent insulin resistance and, as a result, protect your brain as you get older."

A two-decade study

Insulin resistance is a condition in which cells fail to respond normally to the hormone insulin. The resistance prevents muscle, fat, and liver cells from easily absorbing glucose. As a result, the body requires higher levels of insulin to usher glucose into its cells. Without sufficient insulin, excess glucose builds up in the bloodstream, leading to prediabetes, diabetes, and other serious health disorders.

The scientists followed a group of nearly 500 patients with existing cardiovascular disease for more than two decades. They first assessed the patients' baseline insulin resistance using the homeostasis model assessment (HOMA), calculated using fasting blood glucose and fasting insulin levels. Cognitive functions were assessed with a computerized battery of tests that examined memory, executive function, visual spatial processing, and attention. The follow-up assessments were conducted 15 years after the start of the study, then again five years after that.

The study found that individuals who placed in the top quarter of the HOMA index were at an increased risk for poor cognitive performance and accelerated cognitive decline compared to those in the remaining three-quarters of the HOMA index. Adjusting for established cardiovascular risk factors and potentially confounding factors did not diminish these associations.

"This study lends support for more research to test the cognitive benefits of interventions such as exercise, diet, and medications that improve insulin resistance in order to prevent dementia," says Prof. Tanne. The team is currently studying the vascular and non-vascular mechanisms by which insulin resistance may affect cognition.

Article: Insulin Resistance and Future Cognitive Performance and Cognitive Decline in Elderly Patients with Cardiovascular Disease, Lutski, Miri; Weinstein, Galit; Goldbourt, Uri; Tanne, David; Journal of Alzheimer's Disease, doi: 10.3233/JAD-161016, published 21 March 2017.

Brain Loss Slowed in Cognitive 'SuperAgers'

Cognitive "SuperAgers" – those over age 80 with above-average cognitive function – appear to be more resistant to age-related brain shrinkage than their cognitively average peers, researchers found.

While both groups had significant whole-brain cortical volume loss over 18 months, the annual percent change (APC) was significantly greater in the cognitively average elderly compared with SuperAgers (2.24% versus 1.06%, P=0.02), Amanda Cook, MA, of Northwestern University in Chicago, and colleagues reported in a research letter in the Journal of the American Medical Association.

"Our study found that while the brain cortex of both SuperAgers and their cognitively average peers showed shrinkage over 18 months, the rate of cortical brain atrophy in the adult controls was about double that of the SuperAgers," Cook told MedPage Today in an email.

While the effects of this observation are difficult to surmise, differences of this magnitude may have functional consequences, given that this rate of change is similar to that seen in previous studies between non-demented and demented adults over age 50 (e.g., range of APC differences of 0.5%-1.9%), the researchers said.

The study "demonstrates with a specific example that chronological age and biological age are not the same," Nir Barzilai, MD, director of the Albert Einstein College of Medicine Institute for Aging Research, who was not involved in the study, told MedPage Today in an email.

He added, however, that further study is needed to "uncover the biological and genetic explanations for such resiliency. This research reflects the cortical decline, but memory is stored in a different area and the study provides no information for that."

The study, which took place between April 2010 and May 2015, involved 36 individuals with intact daily functioning and stable cognitive status from the community. There were 24 SuperAgers (75% women) and 12 cognitively average elderly adults (42% women) who were similar in age (mean 83 years), levels of education (15 years), and intelligence.

SuperAgers had significantly higher category fluency at the first visit and episodic memory scores at both visits compared with cognitively average elderly adults, Cook said. There were no other significant differences between groups in demographic or neuropsychological measures, including estimated premorbid intelligence and between-visit interval.

Cook cautioned that the possibility that SuperAgers had bigger brains in midlife cannot be ruled out, "as we do not know what their brains looked like 30+ years ago." Previous research by her group showed that at a single time point, the cortex of the SuperAgers was bigger than that of their same-age peers with average memory ability for their age.

She said her study is "relevant in the context of our aging population. Modern medicine has extended the average human life span. However, increasing age is often accompanied by 'typical' cognitive decline or, in some cases ... dementia. SuperAgers suggest that age-related cognitive decline is not inevitable."

While biological health was not assessed in this study, research from the Northwestern University SuperAging Program has not yet found differences between SuperAgers and their cognitively average peers on aspects of physical health (such as diabetes and obesity) or various health behaviors (such as diet, exercise, smoking history, and drinking habits), Cook said.

"Anecdotally, we have SuperAgers who arrive for their study visits with walkers and wheelchairs so their superior cognitive abilities do not necessarily translate into superior physical health," she added.

Cook agreed with Barzilai that more research on this population is needed: "By studying what makes SuperAgers unique, we hope to undercover biological factors, such as the reduced cortical brain atrophy demonstrated here, that may contribute to the maintenance of memory ability in advanced age."

The study was funded by grants from the National Institutes of Health, including the Alzheimer's Disease Core Center, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke, as well as by a grant from the Davee Foundation.

The authors disclosed no financial conflicts of interest.

2017-04-04T13:30:00-0400

• Primary Source

  Journal of the American Medical Association

  Source Reference:
  Cook AH, et al "Rates of cortical atrophy in adults 80 years and older with superior vs average episodic memory" JAMA 2017; DOI: 10.1001/jama.2017.0627.

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Focused Ultrasound Trialed for Alzheimer's Disease

Researchers have successfully used focused beams of ultrasound to open the blood-brain barrier in patients with Alzheimer's disease, the first step in a study to see whether the technology can facilitate ablation of beta-amyloid plaques associated with the illness.

The aim is to make the blood-brain barrier more permeable so as to help amyloid-scavenging drugs such as antibodies reach the plaques.

"We treated the first two Alzheimer's patients yesterday, and things went well. We were able to open the blood-brain barrier successfully," the study's principal investigator, Nir Lipsman, MD, PhD, a neurosurgeon at Sunnybrook Health Sciences Centre in Toronto, said in an email Friday. "Both are doing well so far."

This is the first such use in humans of focused ultrasound to treat Alzheimer's disease, Lipsman said in an interview. The main objective of this phase I trial is to show that the technique is safe.

"If it is safe and technically feasible, subsequent study would combine focused ultrasound with an [anti-amyloid] agent that has trouble crossing the blood-brain barrier," he said. He cited a study in Nature last August that showed in mice that anti-amyloid antibodies can reduce amyloid and stabilize cognitive deficits. "Question is whether enhancing antibody delivery can improve on these results," he said in an email.

Alzheimer specialists not involved in the study were divided over whether this is an appropriate time to begin trials with humans, or whether more work should be done in animals first.

Samuel Gandy, MD, PhD, of Mount Sinai Hospital in New York City, said in an email that while focused ultrasound has been shown to be helpful in treating essential tremor, "brain regions involved in cognition, especially brain regions like the hippocampus that are performing poorly, may not tolerate the insult so well."

Such techniques are better at silencing overactive brain regions than improving function, he said. And he suggested that before moving to human trials, the technique should have been tested in dogs with an Alzheimer's-like condition called CCD (canine cognitive disorder) or in aged nonhuman primates.

Steven DeKosky, MD, of the University of Florida who has worked with Lipsman in the past, disagreed. "I don't think it's premature from the standpoint of the science," he said. Focused ultrasound has been approved for use in the treatment of essential tremor, he said, so "we know the technique can be used in humans safely." He described Lipsman's study as an "extraordinary clever" method of getting anti-Alzheimer medications to their target in the brain.

One concern is whether amyloid plaques could be removed in enough areas of the brain to affect symptoms. "The biggest problem is the cortex is big and the area of focus is small," he said.

David Knopman, MD, of the Mayo Clinic in Rochester, Minn., said he was not familiar with the Lipsman study, but he expressed similar reservations about human trials. Before studies are done in humans, he said, "there should be a clear understanding of what the target is and what the relationship is between the therapeutic target and the desired outcome -- which would be cognitive improvement or cognitive stability."

In this case, he pointed out, the target -- the amyloid plaques -- might have no relationship to the desired outcome.

Lipsman said his study "is the culmination of a few decades of research in animals," including some 200 studies on blood-brain barrier opening with focused ultrasound. "We felt it had reached the threshold where a phase I study was justified."

The study raises two important questions. One is whether it makes sense to go after amyloid when there are questions about the link between amyloid and Alzheimer's disease.

The so-called amyloid hypothesis in Alzheimer's has suffered a series blows in recent clinical trials of anti-amyloid drugs -- none of which have made any impact on cognition in patients with definitely Alzheimer's disease -- but opinion is divided over whether or not it should be abandoned. If the amyloid hypothesis is discarded, Lipsman's study would need to be re-evaluated.

"The amyloid hypothesis has more data by far than any other hypothesis," said DeKosky. "The problem is that there isn't any other hypothesis." Amyloid can appear in the brain years before patients begin showing symptoms. On the other hand, genetic studies have linked mutations in amyloid to Alzheimer's disease symptoms. And the failure of anti-amyloid drugs might simply mean "we have the wrong dose or the wrong drug."

The other question about Lipsman's study concerns the role of the Focused Ultrasound Foundation, based in Charlottesville, Va., which is dedicated to expanding uses of the technology. The group aggressively promotes the use of focused ultrasound for some 80 conditions, including Alzheimer's disease, Parkinson's disease, uterine fibroids, atrial fibrillation, congestive heart failure, depression, diabetes, obesity, cancers of the prostate, kidneys, pancreas, bladder, breast and dozens more illnesses, most at early stages of development.

The foundation is supporting Lipsman's phase I trial, which will include six patients. In the U.S., focused ultrasound has been approved by the FDA for essential tremor, uterine fibroids, pain from bone metastases, and ablation of prostate tissue in cancer or BPH, the foundation says.

The foundation says it spent just under $7 million in 2016 and plans to spend $10.3 million in 2017. It says that 64% of the money raised last year went to research. Most of the funds come from individual donors, it says. It also cooperates with other groups; its $2.2 million Parkinson's disease program received $600,000 in support from the Michael J. Fox Foundation.

1969-12-31T19:00:00-0500

last updated 03.28.2017

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Concern over high US prescribing levels of common drug linked to dementia

A new analysis raises concern over high prescription rates in the USA of a common drug used to treat overactive bladder. The drug, oxybutynin, when taken orally, is consistently linked with cognitive impairment and dementia in the elderly. The analysis shows that oxybutynin, is prescribed in more than a quarter of cases of overactive bladder (27.3%), even though other more suitable drugs are available. This work is presented at the European Association of Urology conference in London, where concerns are also being expressed about the lack of funded alternatives to oxybutynin in Europe.

Overactive bladder (OAB) is extremely common in persons over 65. Initial treatment is normally via behavioural modifications, which can then be followed by first-line medical treatment such as antimuscarinic medications, including oxybutynin. Antimuscarinic drugs are synthetic compounds, originally derived from mushrooms, which block the activity of the muscarinic acetylcholine receptor. They have several uses, including control of OAB. Oxybutynin is the least expensive antimuscarinic used for OAB, and so tends to be the drug of choice for health care plans such as Medicare. However, a body of evidence has shown that oxybutynin is linked to greater cognitive decline in the elderly¹.

An international group of clinicians, led by Dr Daniel Pucheril (Vattikuti Urology Insitute, Henry Ford Hospital, Detroit), looked at evidence from the National Ambulatory Medical Care Survey, where 1,968 patients had received antimuscarinic medications. They found that oxybutynin was prescribed to 27.3% of patients aged over 65 receiving a new antimuscarinic prescription for OAB. Additionally, despite the United States Food and Drug Administration recommendation that patients starting oxybutynin be closely monitored for adverse central nervous system side effects, the authors found that only 9% of elderly persons received a neurologic exam at the time of drug prescription.

Around 16% of US adults suffer from overactive bladder, which translates into tens of millions of sufferers in the US.

According to Dr Pucheril, "We looked at a representative sample, but when you extrapolate to the US population the figures are huge. We estimate that over the six years of our analysis, 47 million individuals in the USA were taking various types of antimuscarinic drugs for OAB, with around 55% of new prescriptions going to the over 65's.

After lifestyle modifications, antimuscarinic medications constitute the most common first line therapies. In the United States, the majority of elderly persons are insured by Medicare. Medicare insurance plans have often have tiered medication formularies to minimize drug expenses. Oxybutynin is the least expensive antimuscarinic drug available, but its pharmacologic properties may cause significant cognitive side effects in elderly persons. Despite evidence of these side effects, physicians are not commonly checking for cognitive effects in those using these medications".

Dr Pucheril continued "We're not saying that everyone should change from oxybutynin to another drug - it still has its uses, and coming off the drug without medical supervision is not recommended. Nevertheless, doctors need to look closely at the levels of prescribing. More than anything else, the funding bodies have to make it easier for doctors to prescribe newer antimuscarinics which are much less likely to cause cognitive dysfunction".

Commenting, on the European situation, Professor Helmut Madsbacher (Innsbruck) said:

"This new work from the US highlights a more general problem which also exists here in Europe. In Europe, oxybutynin use varies from country to country. What we find is that where a range of antimuscarinic drugs is funded, as for example happens in Germany, Austria and Switzerland, then oxybutynin use is low, at around 5% to 7%, for obvious reasons. However, in some countries only oxybutynin is funded, and this creates a problem. For example, the only antimuscarinic funded by Italian health Authorities is oxybutynin, and this leads to some areas with around 70% of antimuscarinic prescriptions being oxybutynin".

Professor Andrea Tubaro (Sapienza Università, Roma) added:

"If an alternative drug is not funded by the health system then it becomes too expensive for a patient to buy themselves. In Italy generic oxybutynin costs around €5/month, but someone wishing to pay for a different antimuscarin or an up-to-date alternative such as a beta3 agonist will end up paying around €50/month. Even in strictly economic terms, there's no sense in saving a few Euros on a drug which risks worsening dementia, one of the most costly conditions which medicine can treat. This is a problem in Italy, but funders in all countries really need to support the use of a range of drugs".

Alzheimer's Disease: Can Money Buy a Cure?

Since the poll posted, responders were divided almost 50-50 on the question, "Is the cost of prescription drugs the main driver of high healthcare costs?"

Physicians call for more Alzheimer's funding.

Now, MedPage Today asks:

2017-04-10T09:00:00-0400

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NIH researchers trace origin of blood-brain barrier 'sentry cells'

Finding in zebrafish may contribute to understanding cognitive decline of aging.

National Institutes of Health researchers studying zebrafish have determined that a population of cells that protect the brain against diseases and harmful substances are not immune cells, as had previously been thought, but instead likely arise from the lining of the circulatory system.

This basic science finding may have implications for understanding age-related decline in brain functioning and how HIV infects brain cells.

The study, appearing online in eLife, was conducted by researchers at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Human Genome Research Institute and the Japanese National Institute of Genetics.

The blood-brain barrier is the layer of cells that line the blood vessels of the brain. The inner cell layer that lines vessels, known as the endothelium, is present in all the blood vessels of the body. Within the blood vessels of the brain, endothelial cells and other adjacent cells form a tight barrier that helps to prevent toxins and microbes from entering the brain. Although their function is not completely understood, a special population of cells covering the blood vessels on the brain's surface is thought to contribute to the organ's protection. The cells act as sentries, engulfing toxins, cellular wastes and microbes and then encasing them in sphere-like structures called vesicles. These sentry cells are called fluorescent granular perithelial cells (FGPs) because the vesicles they contain give off a yellow glow in the presence of light.

In the current study, the researchers showed that FGPs are present on the surface of the zebrafish brain and that these blood vessel-associated FGPs do not arise from the immune system, as had been previously thought, but from endothelial cells themselves.

FGPs are thought to be important in a variety of human brain disorders and conditions. These cells appear to be a major entry point for HIV infection of the brain. Age-related decline in cognitive function is associated with a decline in the scavenging function of FGPs. "Learning more about how FGPs function may lead to a greater understanding of dementia and other conditions," said the study's senior author, Brant Weinstein, Ph.D., of NICHD's Section on Vertebrate Organogenesis.

The Weinstein lab studies zebrafish to understand how the blood and lymphatic systems develop. Because the young fish are transparent, it is possible to see the developing circulatory system while observing the fish under a light microscope. As part of this effort, Dr. Weinstein and his colleagues inserted a gene for a protein that turns green into the cells that line the endothelium of selected embryonic veins and in the lymphatic system - the network of vessels through which immune cells travel in the body. In addition to seeing green lymphatic cells in the zebrafish embryos, the researchers noticed that green cells also covered the surface of the tiny fish's brains.

Upon closer inspection, the researchers tentatively identified these cells as FGPs. Because they turned green, it was apparent that they arose from endothelial cells. Until the current study, FGPs were thought to be macrophages, a type of immune cell. The researchers conducted additional experiments to confirm the origins of the FGPs, including analyzing what proteins were being made by their DNA. These proteins most closely resembled those made by endothelial cells in the lymphatic system, not the proteins made by macrophages or other immune cells. In another series of experiments, they inserted a green fluorescent protein into the tissues that give rise to blood and lymph vessels in embryonic zebrafish. Using time lapse photography, the researchers captured images of FGPs arising from the vessels' endothelium. When zebrafish with the green fluorescing endothelial gene matured, the researchers observed green FGPs on the surface of the fish's brains - confirming that these cells arose from endothelial tissue.

The researchers hope to conduct further studies of how FGPs interact with blood vessels and the blood-brain barrier. The researchers noted that, unlike mammals, embryonic zebrafish can be observed under a microscope as they develop, providing an easy means for studying the role of FGPs in protecting the brain.

Article: A novel perivascular cell population in the zebrafish brain, Marina Venero Galanternik Daniel Castranova Aniket V Gore Nathan H Blewett Hyun Min Jung Amber N Stratman Martha R Kirby James Iben Mayumi F Miller Koichi Kawakami Richard J Maraia Brant M Weinstein, eLife, doi: 10.7554/eLife.24369, published 11 April 2017.

ACP: What to Do About the High Price of Drugs?

SAN DIEGO -- A lack of price controls, inadequate competition, a small market for agents that treat rare diseases, and even the high cost of research are just some of the reasons for the high price-tags of certain drugs, according to speakers here.

During a panel at the American College of Physicians (ACP) meeting, Robert Doherty, ACP senior vice president of governmental affairs and public policy and John Rother, president of the National Coalition on Health Care, discussed the root causes of high-price drugs, their impact on patient care, and strategies for managing the problem.

However, another panelist, Michael Ybarra, MD, senior director of alliance development for the Pharmaceutical Research and Manufacturers of America (PhRMA) offered a different perspective on the price of drugs.

Price Gouging?

Rother noted that some drugs should cost more, but in the case of other agents, such as insulin, "it's value hasn't changed, and yet the price has gone up four or five times," he said.

Moreover, while there are multiple manufacturers of insulin, there's little competition, he added, stating that "what we have here is price collusion or price gouging."

Another example of potential price gouging is deflazacor (Emflaza) for the treatment of for Duchenne muscular dystrophy. Manufacturer Marathon announced a launch price of $89,000 a year in February, despite the drug being being sold for roughly $1,200 a year outside the U.S. The company was forced to freeze the drug's launch after public backlash over its price.

Doherty cited the now infamous Daraprim with a price-tag that rose from $13.50 to $750 overnight as another example of market dysfunction.

When patients can't afford their medicines, they stop taking them, Rother pointed out, and that may lead to worse outcomes and expensive hospital visits.

Usually the generic market is effective in bringing down prices, but there are a handful of generic manufacturers who still price gouge, although there is legislation in the works to discourage that behavior, Rother said.

Higher Healthcare Costs

Asked how drug developers justify charging patients in the U.S. considerably more for drugs than they do patients overseas, Ybarra argued that most healthcare costs overseas are considerably less than the U.S., including hospitalizations. What the U.S. system offers is access to innovation and options for care, he added.

He cited the success of a novel immunotherapy regimen for putting President Jimmy Carter's metastatic melanoma in remission as an example of a novel treatment option available to patients in the U.S., versus in other countries.

Ybarra, who is also an emergency medicine physician, noted that while the list price of insulin has risen, so have rebates. He explained that insulin is a biologic so cannot be chemically synthesized. Creating a biosimilar pathway will be important for competition, he added.

He emphasized that some drugs may seem expensive at face value, but they could offset costs elsewhere, for example by reducing hospitalizations.

Management Measures

The ACP has recommend the following measures to curb drug prices:

• Ask drug companies to disclose their research and development costs
• Establish price transparency standards for drugs developed from tax-payer research
• Allow Medicare to negotiate volume discounts for prescription drugs
• Strike the restrictions on using quality-adjusted life years in comparative research
• Prevent marketing or data exclusivity periods from being further extended
• Enforce rules meant to prevent pay-for-delay practices and "evergreening"

The ACP is lobbying for increased research into ways to encourage value-based decision making, such as bundled payments and evidence-based benefit design.

Ybarra and Rother supported the idea of value-based contracts for drugmakers.

"I think that companies should be on the hook for delivering value for their product," Ybarra stated.

An ACP attendee asked about the concept of a "federal drugmaker" that could product insulin or morphine at a lower cost.

"There's no reason why we can't stop the drug companies from gouging people," said Daniel Berland, MD, of the University of Michigan Medical School in Ann Arbor.

"I think that [idea is] what many people would think of as socialized medicine," Rother told MedPage Today.

2017-04-03T06:58:13-0400

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Different Risks for Amyloid, Neurodegeneration

Action Points

• Protective factors that influence amyloid and __alzheimer disease-pattern neurodegeneration are different, according to a cohort study of 942 elderly individuals enrolled in the Mayo Clinic Study of Aging.
• Note that amyloid deposition and neurodegeneration are the pathophysiologic hallmarks of Alzheimer's disease.

Different factors appear to protect against amyloid deposition and neurodegeneration, the two hallmarks of Alzheimer's disease, according to an analysis from the Mayo Clinic Study of Aging.

Aside from the known risk factors of older age, female gender, and APOE status, only midlife dyslipidemia was associated with amyloid deposition -- while midlife obesity, smoking, diabetes, hypertension, and cardiac and metabolic conditions were tied to neurodegeneration, according to Prashanthi Vemuri, PhD, of the Mayo Clinic in Rochester, Minn., and colleagues.

Intellectual enrichment, however, wasn't a significant predictor of amyloid deposition or neurodegeneration, they reported online in JAMA Neurology.

These data "provide more insight into the complex picture of cognitive aging," Ronald Petersen, MD, PhD, of the Mayo Clinic and a co-author on the paper, told MedPage Today.

Petersen added that the fact that the differences in amyloid deposition and neurodegeneration and how they influence development of Alzheimer's disease "is a hot topic of investigation. The more we learn about the biomarkers, the more we learn about risk and protective factors. The notion of exceptional brain aging is relevant here -- why some people have a lower degree of Alzheimer's disease-causing brain changes even at advanced ages and higher genetic risk of Alzheimer's disease."

For the current study, the researchers analyzed prospective data from 942 individuals ages 70 to 90 from Olmsted County who were enrolled in the Mayo Clinic Study of Aging and had both magnetic resonance imaging (MRI) and Pittsburgh compound B-positron emission tomography (PET) scans. The average age was 80 and 45% of the cohort was female.

Vemuri and colleagues looked at several factors that could potentially be tied to Alzheimer's pathology, including age, sex, APOE status, intellectual enrichment, and midlife risk factors -- physical inactivity, obesity, smoking, diabetes, hypertension, and dyslipidemia -- as well as the total number of late-life cardiac and metabolic conditions.

The association between midlife dyslipidemia and amyloid deposition is consistent with other research, the authors said, suggesting that cholesterol plays an important role in Alzheimer's pathogenesis via amyloid but not neurodegeneration.

Given that other midlife risk factors weren't associated with amyloid deposition, it could be that these are "catalysts for the neuronal processes but not amyloid deposition," they wrote.

Although many midlife risk factors were associated with neurodegeneration, intellectual enrichment was not: "Our work previously showed that the effect of intellectual enrichment on AD biomarkers may be minimal, but that it has a larger effect on delaying the onset of cognitive impairment, suggesting that it is mainly protective against cognitive decline," the researchers wrote.

Individuals age 85 and up who didn't have significant evidence of Alzheimer's pathology (either amyloid or neurodegeneration) were considered "exceptional agers." In this subgroup analysis, there were small-to-moderate effect sizes (Cohen's d >0.2) of several variables except job score and midlife hypertension in predicting exceptional aging without any Alzheimer's disease pathology.

This suggests that protection against both amyloid deposition and neurodegeneration is important, the researchers wrote.

"'Exceptional aging' without ADP may be possible with a greater number of protective factors across the lifespan, but this warrants further investigation," they wrote, adding that study of the independent and combined protective factors for amyloid and neurodegeneration "will enable better prevention strategies to delay the onset and progression of Alzheimer['s] disease."

The study was limited by the fact that it focused on a limited number of protective factors, the groups were not age-matched, and neurodegeneration was a surrogate for tau pathology; future studies should use tau PET imaging, they urged.

Still, Vemuri said the findings reinforce the idea that "advanced age and greater genetic risk of Alzheimer's does not imply that individuals will go on to develop Alzheimer's disease. Therefore, management of overall health of an individual is important for healthier brain aging."

This work was supported by the National Institutes of Health, the Gerald and Henrietta Rauenhorst Foundation, the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation, and the Elsie and Marvin Dekelboum Family Foundation, U.S.A. No conflicts of interest were reported.

• Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College and Dorothy Caputo, MA, BSN, RN, Nurse Planner

2017-04-17T16:30:00-0400

• Primary Source

  JAMA Neurology

  Source Reference: Vemuri, P et al "Evaluation of amyloid protective factors and __alzheimer disease neurodegeneration protective factors in elderly individuals" JAMA Neurol 2017; DOI:10.1001/jamaneurol.2017.0244.

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Study Links Diet Soda to Stroke, Dementia

Action Points

• Note that this observational study found an association between artificially-sweetened beverage intake and stroke and dementia, even after accounting for total caloric intake.
• This does not necessarily imply causality, however, as multiple other confounders may be present.

Higher consumption of artificially sweetened soft drinks was associated with an increased risk of both stroke and dementia in an analysis of more than 4,000 participants in the Framingham Heart Study Offspring cohort, researchers found.

In the observational study, those who drank at least one artificially-sweetened beverage a day were nearly three times more likely to develop ischemic stroke (HR 2.96, 95% CI 1.26–6.97) and 2.9 times more likely to develop Alzheimer's disease (95% CI 1.18–7.07) over 10 years than those who abstained, Matthew Pase, PhD, of Boston University School of Medicine, and colleagues reported in the American Heart Association's journal Stroke.

However, sugary beverages weren't tied to an increased risk of stroke or dementia -- a finding the authors called "intriguing," and one that could have been due to survival bias.

"It is possible that individuals with high intakes of sugary beverages may have died earlier from other illnesses such as heart disease," Pase told MedPage Today. "It is also worth noting that our sample consumed diet soda more frequently than sugar-sweetened soda and this may contribute to differences in findings between regular and diet soda."

He cautioned that the association between artificially sweetened drinks and stroke and dementia seen in their study does not imply causation -- a point emphasized by Marion Nestle, PhD, professor of nutrition, food studies, and public health at New York University, who wasn't involved in the study.

"Association is not the same as causation, although the survival curves are impressive," Nestle said. "I wish the authors had offered a plausible hypothesis for how artificial sweeteners could be causally related to stroke and dementia."

Several other experts commented on the "controversial but inconclusive" nature of the association.

"The relationship with artificially sweetened beverages was not simple or straightforward," said Keith Fargo, PhD, of the Alzheimer's Association. "When the researchers controlled for other risk factors, particularly cardiovascular risk factors, it explained most of the association between artificially sweetened beverage intake and the development of dementia. This kind of data does not allow us to say that drinking [these] beverages causes dementia, or that cutting down on artificially sweetened beverages will reduce a person's risk for dementia."

Pase and colleagues analyzed data from the Framingham Heart Study Offspring cohort on people over age 45 years for the stroke arm (N=2,888) and people over age 60 years for the dementia arm (N=1,484). Both groups were primarily Caucasian and were just under 50% male.

Beverage intake was quantified using the Harvard semiquantitative food-frequency questionnaire at three points: cohort examinations five (1991–1995), six (1995–1998), and seven (1998–2001). Participants were then followed for more than 10 years to determine development of stroke or dementia.

Notably, data collection did not distinguish between the types of artificial sweeteners used in the beverages.

Pase and colleagues found that higher recent and cumulative intake of artificially sweetened soft drinks was linked to an increased risk of ischemic stroke, all-cause dementia, and Alzheimer's dementia -- even after adjustment for total caloric intake, diet quality, physical activity, and smoking status.

However, the associations between recent and higher cumulative intake of artificially sweetened soft drinks and dementia were no longer significant after additional adjustment for vascular risk factors and diabetes mellitus.

"Because our study was observational, we are unable to determine whether artificially sweetened soft drink intake increased the risk of incident dementia through diabetes mellitus or whether people with diabetes mellitus were simply more likely to consume diet beverages," Pase said.

Pase noted the findings complement their sister study, published in Alzheimer's & Dementia, that found higher consumption of both sugary and diet beverages was associated with smaller brain volumes, a marker of accelerated brain aging.

Also using data from the Framingham Heart Study Offspring cohort, this study found that people who more frequently consumed sugary beverages, including sodas and fruit juices, were more likely to have poorer memory, smaller overall brain volumes, and smaller hippocampal volumes.

The researchers concluded that their studies highlight a need for more research into this area, especially given how often people drink artificially-sweetened beverages.

In an accompanying editorial in Stroke, Ralph Sacco, MD, of the University of Miami Miller School of Medicine, agreed, writing that the findings "encourage further discussion and more research into this question, for even small causal effects would have tremendous effects on public health due to the popularity of both artificially sweetened soft drinks and sugar sweetened soft drinks consumption. Both sugar-sweetened and artificially sweetened soft drinks may be hard on the brain."

"This kind of research is critical for examining and uncovering public health relationships that may eventually lead to actionable recommendations," added Fargo.

Rachel Johnson, PhD, MPH, RD, past chair of the American Heart Association's Nutrition Committee and professor at the University of Vermont, suggested that people stick to water, low-fat milk, or other beverages without added sweeteners until more data are available: "We know that limiting added sugars is an important strategy to support good nutrition and healthy body weights, and until we know more, people should use artificially sweetened drinks cautiously," she said in a statement.

The researchers acknowledged several study limitations, including the observational nature of the data, the absence of ethnic minorities, and the use of a self-reported questionnaire to obtain dietary intake data, which may be subject to recall bias.

"Even if someone is three times as likely to develop stroke or dementia," Pase said, "it is by no means a certain fate."

Pase reported funding from the National Health and Medical Research Council.

The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute and by grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.

Sacco received a National Institutes of Health grant for the Northern Manhattan Study. Gardener is also funded by the National Institutes of Health for her work on the Northern Manhattan Study.

• Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

2017-04-20T16:00:00-0400

• Primary Source

  Stroke

  Source Reference: Pase M, et al "Sugar and artificially sweetened beverages and the risks of incident stroke and dementia a prospective cohort study" Stroke 2017; DOI: 10.1161/STROKEAHA.116.016027.

• Secondary Source

  Stroke

  Source Reference: Wersching H, et al "Sugar-sweetened and artificially sweetened beverages in relation to stroke and dementia are soft drinks hard on the brain?" Stroke 2017; DOI: 10.1161/STROKEAHA.117.017198.

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Cord Blood Protein Boosts Memory in Old Mice (Tech Times)

Infusion of umbilical-cord blood containing a naturally occurring protein led to improvement in memory and cognitive function in aged mice, as reported by Tech Times.

Elderly mice, equivalent in human age to 70 years old, performed a series of memory and cognitive tasks before and after infusion of cord blood-derived plasma. The animals' test performance improved substantially after the infusion. Test performance also improved in animals that received plasma from young adult humans (median age 22). In contrast, the animals' test performance did not change after receiving plasma from older adults (median age 66).

Researchers traced the cognitive improvement to a specific protein in the plasma: tissue inhibitor of metalloproteinase 2 (TIMP-2). However, timing and mechanism of TIMP-2 production remained unclear, and the researchers, reporting in Nature, cautioned that success in animal studies often does not translate to human studies.

2017-04-20T16:00:00-0400

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How Sensory Stimulation Can Help Alzheimer’s

Originally used as a therapy in Europe, sensory stimulation has gained prominence in the United States as a treatment for Alzheimer’s disease.

Using everyday objects, therapists can trigger emotions and memories in seniors who have lost their ability to connect with the world around them.

Sensory Stimulation Therapy

Sensory stimulation uses everyday objects to arouse one or more of the five senses (hearing, sight, smell, taste and touch), with the goal of evoking positive feelings.

Used in Europe since the 1960s, this therapy was originally designed to help people with learning disabilities. It was a way for them to explore a safe, stimulating environment that provided age-appropriate and enjoyable activity.

Since then, the therapy has become widely used to treat other conditions, including:

• Alzheimer’s
• Autism
• Brain injuries
• Chronic pain
• Other forms of dementia

Ways Sensory Stimulation Can Affect Alzheimer’s

As Alzheimer’s progresses, a senior’s ability to communicate and perform everyday activities declines. Giving these seniors means to express themselves, when they can no longer do so with words, can help them feel safe and relax. This can improve their:

1. Mood
2. Self-esteem
3. Well-being

Additionally, by drawing attention to a particular item, sensory stimulation encourages memories and responses from seniors suffering from Alzheimer’s:

For instance, art or photos can trigger emotions and memories for seniors who no longer speak. A senior who has not expressed a word in months might suddenly smile or want to pick up a pencil and draw. That art form eventually can become a means for the senior to communicate, either through personal works of art or simply by sharing the experience.

Ways Sensory Stimulation Engages Seniors

Sudden drops in blood pressure may increase risk of dementia

Dementia affects tens of millions of people in the United States. New research suggests that those who experience sudden blood pressure drops in their middle age may be more likely to develop dementia in old age.

New research finds long-term link between sudden drops in BP and the risk of dementia in later life.

Alzheimer's disease, the most common form of dementia, currently ranks as the sixth leading cause of death in the U.S. In fact, it is estimated that 1 in 3 U.S. elders dies with a form of dementia.

New research indicates that middle-aged people who experience sudden drops in their blood pressure (BP) may be at risk of developing dementia and serious cognitive decline when they reach old age.

The study was conducted by researchers from the Johns Hopkins Bloomberg School of Public Health in Baltimore, MD, and the findings were presented at the American Heart Association's Epidemiology and Prevention/Lifestyle 2017 Scientific Sessions in Portland, OR.

Chronically low BP may cause dizziness, fatigue, nausea, or fainting. Temporary, rapid drops in BP bear the name "orthostatic hypotension" (OP) and may cause serious damage; they stop the necessary blood flow from reaching the brain.

Previous studies have indicated a link between OP and cognitive impairment in seniors, but the new Johns Hopkins study - led by Andreea Rawlings, Ph.D., a post-doctoral researcher in the Department of Epidemiology at the Bloomberg School - is the first to examine the long-term correlations between the two.

The researchers examined clinical data from the Atherosclerosis Risk in Communities study, which collected information on 15,792 participants aged between 45 and 64 in 1987, the year of enrollment.

Patients with OP are 40 percent more likely to have dementia

For the new study, Rawlings and team isolated the data on 11,503 patients who had no history of heart disease and visited the hospital for the first time. Scientists took the patients' BP after they had lay down for 20 minutes.

The researchers defined OP as a rapid drop of 20 millimeters of mercury (mm Hg) or more in systolic BP, or 10 mm Hg or above in diastolic BP.

Approximately 6 percent of the participants, or 703 individuals, met these criteria.

The team clinically followed the participants for the following two decades or more.

They found that people with OP upon their first visit had a 40 higher risk of developing dementia than their OP-free counterparts. Patients with OP also had 15 percent more cognitive decline.

"Even though these episodes are fleeting, they may have impacts that are long lasting. We found that those people who suffered from orthostatic hypotension in middle age were 40 percent more likely to develop dementia than those who did not. It is a significant finding and we need to better understand just what is happening."

Andreea Rawlings, lead author

As this is an observational study, researchers cannot establish causality or explain whether OP is an indicator of another disease responsible for the cognitive decline. However, they speculate that the decrease in the blood flow to the brain may play a role.

The lead author of the study also acknowledges the study's limitation that arises from not knowing whether the patients had a singular episode of OP, or whether they had lived with the recurring symptoms over time.

"Identifying risk factors for cognitive decline and dementia is important for understanding disease progression, and being able to identify those most at risk gives us possible strategies for prevention and intervention," Rawlings says. "This is one of those factors worth more investigation."

Learn how high BP is linked to a lower risk of Alzheimer's.

Written by Ana Sandoiu

Seniors Load Up on Psych Meds (JAMA Internal Medicine)

Older Americans are being over-prescribed, suggested new research finding that the percentage of people over 65 taking three or more mind-altering drugs has more than doubled in the past decade.

What's more, nearly half of these patients were not formally diagnosed with mental health issues, insomnia, or pain conditions.

Researchers found that 1.4% of doctor visits by seniors involved three or more central nervous system-affecting medication in 2013 compared to 0.6% in 2004, meaning 3.68 million doctor visits a year involve older patients taking three or more brain-altering drugs.

The authors said the latest findings are "concerning" as combining multiple drugs such as opioids, antidepressants, tranquilizers, and antipsychotics are associated with serious risks, particularly in seniors.

"We hope that the newer prescribing guidelines for older adults encourage providers and patients to reconsider the potential risks and benefits from these combinations," said lead author Donovan Maust, MD, MS, of the University of Michigan.

2017-02-15T15:30:00-0500

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FDA Clears App to Screen for Cognitive Impairment

The FDA recently granted UK-based Cambridge Cognition Holdings 501(k) clearance to market CANTAB Mobile as a device that can detect early stages of clinically relevant mental impairment in older adults.

For older adults, early detection of dementia and Alzheimer's is crucial for receiving timely treatment and planning the future. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was developed initially more than 30 years ago as a group of tests for use in neurologic and psychiatric research. The Paired Associates Learning (PAL) test is one of the tests to detect features of cognitive impairment that could be signs of early Alzheimer's disease.

CANTAB Mobile translates the relatively complex, specialist-administered PAL test into a self-guided, iPad-based exam that can be administered at a larger scale, such as in a primary care office or as part of large clinical studies.

Assessment via the medical app is a simple, 10-minute, point-of-care exam anyone can use anywhere. CANTAB Mobile's platform includes three tests focused on episodic memory, mood, and the ability to perform regular, daily activities. The test also takes age, gender, and education into consideration, and results, in the form of a 1-page physician's report, can reassure the user or refer patients to next steps.

We've seen some other examples of neurologic and psychiatric assessment tools being translated into mobile platforms. One example is the HAND in HAND ResearchKit app from the University of Nebraska, which focused on the cognitive impacts of chronic HIV. In that study, a platform called Brain Baseline was used to offer plug-and-play neurologic assessments.

According to a description of CANTAB Mobile in Translational Neuropsychopharmacology (Robbins et al, Springer, 2016) by researchers from Cambridge Cognition Holdings, about 25% of ~10,000 patients screened in the UK were identified as having clinically significant memory problems. Hopefully, we'll see more data on the real-world accuracy of large-scale screening using CANTAB Mobile, and the downstream effects of that.

This post originally appeared on iMedicalApps.com.

2017-03-10T15:00:00-0500

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ACC: FOURIER Substudy May Help Refute 'Dr. Google'

WASHINGTON -- Reaching very low LDL levels with a PCSK9 inhibitor was not associated with any increase in neurocognitive adverse events, according to the largest and most rigorous study to assess the topic to date.

Small and preliminary studies have raised concerns over the possibility of the neurocognitive effects of statins. Though most clinicians and scientists have not shared these concerns, consumers and patients have expressed broad suspicions about statins.

"In my office every day my patients say that statins make them dumb. I can comfortably tell my patients that we actually studied whether this makes you dumb, and it didn't," said Sandra Lewis (Oregon Health and Science University).

The new study, called EBBINGHAUS, was a substudy of the enormous FOURIER trial, published Friday, which compared the cardiovascular event impact of PCSK9 inhibition with evolocumab (Repatha) or placebo. EBBINGHAUS tested the hypothesis that "the addition of evolocumab to statin therapy in patients with clinically evident vascular disease does not adversely affect cognitive function."

The results were presented at the American College of Cardiology meeting here by Robert Giugliano (Brigham & Women's Hospital). "We all need your help to combat Dr. Google," he told the media at a press conference.

EBBINGHAUS enrolled 1,974 patients from the FOURIER trial. The primary analysis was based on the cohort of 1,204 patients who had baseline and follow-up cognitive testing, consisting of a battery of tests, patient surveys, and investigator-reported adverse events. There were no significant differences between the groups in the primary endpoint, the spatial working memory strategy index, or any of the other measures in the study.

"It's out there on the internet that statins make people stupid," said Roger Blumenthal (Johns Hopkins), a trial discussant. EBBINGHAUS "advanced the field by showing that pharmacologically achieved low levels of LDL are safe," he said. But Giugliano and others acknowledged that the trial tested the effect of a PCSK9 inhibitor and did not assess the effects of statins, which are much more widely used. But the lack of adverse effects in patients reaching extremely low LDL levels (30 mg/dL) in the FOURIER trial will likely add much reassurance.

Giugliano reported that there were no differences between older and younger patients in EBBINGHAUS. But the trial did not address the concerns that have been raised about the effects of very long-term lipid-lowering therapy for primary prevention.

2017-03-19T10:18:13-0400

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