What's good for the heart is good for the brain

by American Heart Association

Credit: Pixabay/CC0 Public Domain

The same risk factors that contribute to making heart disease the leading cause of death worldwide also impact the rising global prevalence of brain disease, including stroke, Alzheimer's disease and dementia, according to the American Heart Association's Heart Disease and Stroke Statistics—2022 Update, published today in the Association's flagship, peer-reviewed journal Circulation. Experts say maintaining a healthy weight, managing your blood pressure and following other heart-healthy lifestyle behaviors can also support good brain health.

29 jan 2022--Optimal brain health includes the functional ability to perform all the diverse tasks for which the brain is responsible, including movement, perception, learning and memory, communication, problem solving, judgment, decision making and emotion. Cognitive decline and dementia are often seen following stroke and cerebrovascular disease and indicate a decline in brain health. Conversely, studies show maintaining good vascular health is associated with healthy aging and retained cognitive function.

The global death rate from Alzheimer's disease and other dementias is increasing considerably—even more than the rate of heart disease death:

• Globally, more than 54 million people had Alzheimer's disease and other dementias in 2020, that's a 37% increase since 2010 and a 144% increase over the past 30 years (1990-2020).
• More than 1.89 million deaths were attributed to Alzheimer's disease and other dementias worldwide in 2020, compared to nearly 9 million deaths from heart disease.
• Global deaths from Alzheimer's disease and other dementias increased more than 44% from 2010 to 2020, compared to a 21% increase in deaths from heart disease.
• Deaths from Alzheimer's disease and other dementias increased 184% over the past 30 years (1990-2020), compared to a 66% increase in heart disease deaths during that same time.

Because prevalence and mortality data are tracked differently by the Centers for Disease Control and Prevention, in the U.S. compared to other countries, the Statistical Update does not offer comparable national data for 2020. However, nearly 2.9 million people in the U.S. were reported to have Alzheimer's disease and other dementias in 2017. Alzheimer's disease and other dementias combined were the leading cause of death among all neurological disorders, including stroke.

"The global rate of brain disease is quickly outpacing heart disease. The rate of deaths from Alzheimer's disease and other dementias rose more than twice as much in the past decade compared to the rate of deaths from heart disease, and that is something we must address," said Mitchell S.V. Elkind, M.D. M.S., FAHA, the immediate past president of the American Heart Association, a professor of neurology and epidemiology at Columbia University Vagelos College of Physicians and Surgeons and attending neurologist at New York-Presbyterian/Columbia University Irving Medical Center, New York, NY. "We are learning more about how some types of dementia are related to the aging, and how some types are due to poor vascular health. Many studies show that the same healthy lifestyle behaviors that can help improve a person's heart health can also preserve or even improve their brain health. It's becoming more evident that reducing vascular disease risk factors can make a real difference in helping people live longer, healthier lives, free of heart disease and brain disease."

The 2022 Statistical Update highlights some of that research:

• In a meta-analysis of 139 studies, people with midlife hypertension were five times more likely to experience impairment on global cognition and about twice as likely to experience reduced executive function, dementia and Alzheimer's disease.
• Nearly half of all adults (47% or 121.5 million) in the U.S. have elevated blood pressure, based on 2015 to 2018 data.
• In a meta-analysis of longitudinal studies with up to 42 years of follow-up, people with obesity had three times the risk of dementia.
• Current smoking was associated with a 30%-40% increased risk of dementia, Alzheimer's disease and vascular dementia, based on a meta-analysis of 37 prospective studies.

Having cardiovascular disease also increases the chances of developing brain disease:

• In a meta-analysis of four longitudinal studies, the risk for dementia associated with heart failure was nearly two-fold.
• In the ARIC Neurocognitive study (12,515 participants, average age of 57 years, 24% Black participants, 56% women), atrial fibrillation was associated with greater cognitive decline and dementia over 20 years.
• A meta-analysis of 10 prospective studies (including 24,801 participants) found that coronary heart disease was associated with a 40% increased risk of poor cognitive outcomes including dementia, cognitive impairment or cognitive decline.

There are also significant differences in the gender, race/ethnicity and socioeconomic status of people who are more likely to develop brain disease and dementia, an indication that social determinants of health also play a role:

• Of the more than 54 million cases of Alzheimer's disease and other dementias worldwide in 2020, almost 20 million were among men, compared to nearly 35 million women. More than twice as many women as men died from Alzheimer's disease and other dementias.
• A retrospective analysis of the 2016 Behavioral Risk Factor Surveillance System data found significant differences in subjective cognitive decline across non-white racial and ethnic groups when compared to white adults in the 20,843 respondents who reported being diagnosed with stroke. Compared to white adults, other racial and ethnic groups were more likely to report worsening confusion or memory loss that contributed to not participating in everyday activities or difficulty with work, volunteer, and social activities outside of the home at least some of the time. After adjustments for sex, age, education, income and comorbidities, Black adults were one-and-a-half times more likely and Hispanic adults were more than twice as likely than white adults to give up day-to-day household activities or chores because of confusion or memory loss. Black adults were almost three times as likely and Hispanic adults were more than four times as likely to report needing assistance with everyday activities compared to white adults. These findings are likely due to social determinants of health negatively impacting communities of color over their lifetime, advised Elkind.

Estimated U.S spending on dementias more than doubled from $38.6 billion in 1996 to $79.2 billion in 2016. Spending on dementias was among the top 10 health care costs in the United States in 2016.

"Like cardiovascular disease, Alzheimer's disease, dementia and other cognitive ailments are a tremendous emotional and economic burden across the globe," said Connie W. Tsao, M.D., M.P.H., FAHA, chair of the Statistical Update writing group, assistant professor of medicine at Harvard Medical School and attending staff cardiologist at Beth Israel Deaconess Medical Center in Boston. "This new chapter on brain health was a critical one to add. The data we've collected brings to light the strong correlations between heart health and brain health and makes it an easy story to tell—what's good for the heart is good for the brain."

Over the past several years, the American Heart Association has supported more than $46 million in research funding focused on brain health. In a $43 million collaboration with The Paul G. Allen Frontiers Group, the Association is funding three projects that are now underway to find innovative ways to understand and improve brain health and cognitive impairment science. A $3.3 million grant in collaboration with global philanthropist and technology visionary Bill Gates is committed to advancing the scientific evidence base related to brain health and dementia. The project supports a new brain health and dementia technology research center at Boston University. Additionally, it will support the global exchange of research data to help scientists around the world collectively work in accelerating new discoveries related to heart and brain health, including the early detection and treatment of Alzheimer's disease and related dementias.

"Advancing brain science through innovative research will help scientists shed new light on the causes and contributors to cognitive impairment and dementia, particularly as it relates to heart and vascular health. This is an important step in the Association's ongoing commitment to better understand how our brains age and how vascular health impacts brain health and overall well-being," said Elkind, who is a member of the Statistical Update writing committee. "Additionally, it's critical that as a society and as individuals we understand and make the changes needed to improve health outcomes from brain disease and, more importantly, prevent them to begin with."

Along with new information on brain health, the 2022 Statistical Update provides the latest available data on key factors related to heart disease and stroke:

• On average, someone dies of cardiovascular disease (CVD) every 36 seconds in the U.S. There are 2,396 deaths from CVD each day, based on 2019 data.
• On average, someone in the U.S. has a stroke every 40 seconds. There are about 795,000 new or recurrent strokes each year, based on 1999 data.
• On average, someone dies of a stroke every 3 minutes and 30 seconds in the U.S. There are about 411 deaths from stroke each day, based on 2019 data.
• Approximately 1 in 4 (24%) U.S. adults reported achieving adequate leisure-time aerobic and muscle-strengthening activities to meet the physical activity guidelines, based on 2018 data.
• 1 in 7 male adults and 1 in 8 female adults in the U.S. are current smokers, based on 2019 data.

Tracking such trends is one of the reasons the American Heart Association publishes the definitive statistical update annually, providing a comprehensive resource of the most current data, relevant scientific findings and assessment of the impact of cardiovascular disease nationally and globally.

The U.S. data is gathered in conjunction with the National Institutes of Health and other government agencies, while the global trends are provided by the Global Burden of Disease Study from the Institute for Health Metrics and Evaluation at the University of Washington.

The annual update represents a compilation of the newest, most relevant statistics on heart disease, stroke and risk factors impacting cardiovascular health. It tracks trends related to ideal cardiovascular health, social determinants of health, global cardiovascular health, cardiovascular health genetics and health care costs. Tsao emphasized the importance of this surveillance as a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates and others seeking the best available data on these factors and conditions.

This statistical update was prepared by a volunteer writing group on behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee.

More information: Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association, Circulation (2022). DOI: 10.1161/CIR.0000000000001052

Many patients with iNPH develop Alzheimer's disease, too

by University of Eastern Finland

Credit: CC0 Public Domain

Up to one in five patients treated for idiopathic normal pressure hydrocephalus, iNPH, also develop Alzheimer's disease, according to a new study from the University of Eastern Finland and Kuopio University Hospital. The researchers were able to predict the development of Alzheimer's disease by using the Disease State Index, DSI, that combines patient-specific data from various sources. The results were published in Journal of Alzheimer's Disease.

15 nov 2019--In iNPH, the circulation of cerebrospinal fluid (CSF) is disturbed for an unknown reason, leading to a slightly elevated brain pressure and dilation of the brain ventricles. Symptoms of NPH include gait deviations, impaired short-term memory and urinary incontinence. Patients with iNPH often have changes in brain that are related to Alzheimer's disease.

The study followed patients with iNPH after they had received treatment for their disease. They were treated with shunt surgery, in which excessive CSF is drained from the brain ventricles to the abdominal cavity by using a CSF shunt. Shunted NPH patients who had undergone brain tissue biopsy in connection with their surgery were selected for the study. The objective of the biopsy was to detect changes that are indicative of Alzheimer's disease.

During the follow-up, the researchers found that up to one in five patients with NPH were later diagnosed with Alzheimer's disease. At the end of the follow-up, patients with NPH were more frequently diagnosed with Alzheimer's disease than the general population. The researchers were able to predict the development of Alzheimer's disease, with moderate accuracy, by using patient-specific DSI. The data used in DSI included the patient's pre-surgery symptom profile, brain tissue samples and brain MRI images.

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More information: Antti J. Luikku et al, Predicting Development of Alzheimer's Disease in Patients with Shunted Idiopathic Normal Pressure Hydrocephalus, Journal of Alzheimer's Disease (2019). DOI: 10.3233/JAD-190334

Journal information: Journal of Alzheimer's Disease 

Provided by University of Eastern Finland 

Alzheimer's disease: have we got the cause all wrong?

by Vicky Jones, The Conversation

Credit: Fer Gregory/Shutterstock

Early in the 20th century, Alois Alzheimer first described a disorder of progressive memory loss and confusion in a 50-year-old woman. After she died, he examined her brain and saw that it was full of unusual protein clumps, known as plaques. Over a century later, we know that these plaques are full of a protein called beta-amyloid and are a hallmark of the disease that bears Alzheimer's name. While other features of Alzheimer's disease have been discovered, the theory that beta-amyloid is the main cause of this incurable disease has dominated.

28 mar 2019--There are many subtle variations of the "beta-amyloid hypothesis", but generally the theory goes that beta-amyloid accumulates in the brain, then clumps together. Somewhere in this process, nerve cells in the brain become damaged, which leads to memory loss and other symptoms of Alzheimer's disease. So the approach to treating this should be rather straightforward: stop the clumping and you will halt the disease.

Unfortunately, decades of research, many millions of dollars of investment and many failed clinical trials later, it appears that this approach is not working. The most recent plaque-busting treatment to produce disappointing results has been aducanumab – an antibody-based therapy designed to stick to and destroy beta-amyloid.

Initial data suggested that the treatment did, indeed, clear beta-amyloid from the brain. But this week, Biogen and Esai, the drug companies behind aducanumab, ended clinical trials involving thousands of patients early, stating that the "trials were unlikely to meet their primary endpoint upon completion".

This has led many to ask whether the amyloid hypothesis of Alzheimer's disease should be abandoned. In reality, few neuroscientists still subscribe to the view that it is the beta-amyloid plaques themselves that cause the symptoms of Alzheimer's disease.

Studies with mice that mimic human Alzheimer's disease have shown that memory loss occurs before plaques form in the brain. Other studies have suggested that it is the smaller fragments ("oligomers") of beta-amyloid that are really toxic to nerve cells. And it has even been suggested that the formation of plaques is a way for the brain to round-up all these dangerous oligomers into one place for safety.

It's very hard to tell without the full information from the aducanumab trial, but maybe the disease had progressed too far in the participants for the treatment to be effective. Perhaps the small beta-amyloid oligomers had already done their damage, setting the disease in motion before the participants were even recruited to the trial.

Amyloid-beta plaques (yellow) clumping around brain cells (blue). Credit: Juan Gaertner/Shuterstock

Alzheimer's disease vs Alzheimer's dementia

At a recent Alzheimer's Research UK Conference, there was near universal agreement that it's time to separate the concept of Alzheimer's disease from the menace of dementia.

Alzheimer's disease is defined as the build up of beta-amyloid plaques and tangles of another protein, tau, combined with some mild memory changes. Dementia is a symptom of this disease. Advances in brain imaging mean that doctors can now spot these indicators of Alzheimer's disease much earlier (up to 25 years before dementia symptoms set in). An astonishingly under-reported fact is that progression to dementia is not a given. Not all people who show these clinical signs of Alzheimer's disease will progress to dementia in their lifetimes.

We are only beginning to study the reasons that some people with Alzheimer's disease avoid Alzheimer's dementia. Age is the single biggest risk factor for this progression; the younger you are when beta-amyloid starts to build up in the brain, the more likely you are to suffer from dementia. Diet, education and head injuriesmay also play a role in this process, but to what extent we do not know.

Another major factor we are only just beginning to understand is genetics. Small variations in our genes seem to influence not only whether we will get a build up of beta-amyloid in the brain, but whether that accumulation leads to dementia symptoms.

The process of finding these so-called "risk genes", however, is slow. Progress has mostly come from "big data" studies that track tiny changes in the two billion odd DNA bases of the human genome across tens of thousands of individuals and try to find patterns between these changes and rates of Alzheimer's.

There are around 30 areas of the human genome that have been linked to the risk of developing Alzheimer's dementia, although there are certainly more to be discovered.

Aducanumab: right treatment, wrong time?

As with treatments for many other human diseases, it might be that treatments such as aducanumab might only be effective if they are given early enough, before the disease has caused irreversible changes. A better understanding of the environmental and genetic factors behind Alzheimer's disease combined with ever more sensitive brain imaging techniques will help doctors identify warning signs even earlier, before even minor memory loss occurs.

While screening and diagnosing people – before symptoms have set in – for an as-yet incurable disease, raises many ethical dilemmas, it might present a fresh window of opportunity to retest beta-amyloid drugs, such as aducanumab. Ultimately, we need to focus our research on understanding the early stages of the disease so that we can prevent Alzheimer's disease before dementia takes hold.

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Provided by The Conversation

Researchers classify Alzheimer's patients in six subgroups

Genetic data supported the contention that a particular way of sorting people resulted in biologically coherent subgroups (pictured lower right). Credit: University of Washington School of Medicine

Researchers studying Alzheimer's disease have created an approach to classify patients with Alzheimer's disease, a finding that may open the door for personalized treatments.

07 dec 2018--"Alzheimer's, like breast cancer, is not one disease," said lead author Shubhabrata Mukherjee, research assistant professor in general internal medicine at the University of Washington School of Medicine. "I think a good drug might fail in a clinical trial because not all the subjects have the same kind of Alzheimer's.
This study, published in the recent issue of Molecular Psychiatry, involves 19 researchers from several institutions, including Boston University School of Medicine, the VA Puget Sound Health Care System and Indiana University School of Medicine.
The researchers put 4,050 people with late-onset Alzheimer's disease into six groups based on their cognitive functioning at the time of diagnosis and then used genetic data to find biological differences across these groups.
"The implications are exciting," said corresponding author Paul Crane, professor of general internal medicine at the University of Washington School of Medicine. "We have found substantial biological differences among cognitively defined subgroups of Alzheimer's patients."
Identification of cognitive subgroups related to genetic differences is an important step toward developing a precision medicine approach for Alzheimer's disease.
The participants received cognitive scores in four domains: memory, executive functioning, language, and visuospatial functioning.
The largest group (39%) had scores in all four domains that were fairly close to each other. The next largest group (27%) had memory scores substantially lower than their other scores. Smaller groups had language scores substantially lower than their other scores (13%), visuospatial functioning scores substantially lower than their other scores (12%), and executive functioning scores substantially lower than their other scores (3%). There were 6% who had two domains that were substantially lower than their other scores.
The participants came from five studies, and it took more than two years to standardize the neuropsychological test scores across all the studies in order to detect meaningful patterns. The mean age was 80, 92 percent self-reported white race, and 61 percent were female.
The investigators used genome-wide genetic data to find out if the subgroups are biologically distinct.
Investigators found 33 single nucleotide polymorphisms (SNPs) - specific locations throughout the genome—where the genetic association was very strong for one of the subgroups. These genetic relationships were stronger than the strongest effects found by an earlier and much larger international consortium study where Alzheimer's disease was treated as a single homogeneous condition.
Several years ago, the International Genomics of Alzheimer's Project Consortium published the largest genome-wide association study of Alzheimer's disease and found about 20 SNPs associated with Alzheimer's disease risk.
This study found 33 additional SNPs with even stronger relationships with a single subgroup.
The study also found a particularly strong relationship between a particular variant of the APOE gene and risk for the memory subgroup. The APOE e4 allele is a very strong risk factor for developing Alzheimer's disease for people with European ancestry, and it also appears to influence which cognitive subtype of Alzheimer's a person is likely to develop.
People can currently find out if they have an APOE e4 allele with direct-to-consumer testing; however, the researchers note that many people with an APOE e4 allele never develop Alzheimer's disease, and many who don't carry any known genetic risk factor nevertheless end up with the condition.
While world leaders want to find a cure for Alzheimer's by 2025, so far no one has been able to develop an effective treatment let alone a cure. But this study suggests that thinking of Alzheimer's disease as six distinct conditions may provide a way forward.
"This study is not the end, it's a start," said Mukherjee.

More information: et al, Genetic data and cognitively defined late-onset Alzheimer's disease subgroups, Molecular Psychiatry (2018). DOI: 10.1038/s41380-018-0298-8


Provided by University of Washington

Disrupted rest and activity patterns could be an early indicator of Alzheimer's

Scientists from the US have found a link between certain biological fingerprints thought to indicate early stages of Alzheimer's and sleep disturbances. Their findings are published today in JAMA Neurology.
Links between poor sleep and dementia have been known of for some time but teasing out the precise cause and effect relationship is difficult – does poor sleep contribute to developing dementia, or is it that poor sleep is an early indicator of the condition?

04 feb 2018--To try to understand this relationship, a team of researchers from Washington University studied a group of 186 volunteers, using wearable activity monitors (actigraphy) day and night to measure periods of rest and activity as this group went about their normal daily lives in their homes. The study participants were all over the age of 45 (mean age, 66), and did not have any problems with memory or thinking. Participants (155 people) had donated samples of spinal fluid, in which the researchers measured the levels of two Alzheimer's proteins, tau and amyloid. Some participants (142 people) had also undergone specialised brain scans to measure the level of amyloid in their brain, called a PiB-PET scan.
The researchers found that increasing age was linked with decreased sleep quality, shown by a fragmenting of normal rest-activity patterns, such as increased napping during the day and being awake during the night. Looking at the brain scans, the researchers set a level to determine which scans showed amyloid build-up, finding 26 people showed amyloid high levels of amyloid in their brains and 116 people did not.
When they compared the two groups, the scientists found that people with amyloid build-up showed more fragmented rest-activity patterns, even when age and sex were taken into account. Similarly, people with an increased ratio of tau to amyloid in their spinal fluid, indicative of early Alzheimer's changes, were also found to have fragmented rest-activity patterns.
Dr. David Reynolds, Chief Scientific Officer at Alzheimer's Research UK, said:
"Research has faced a bit of a chicken and egg situation when looking at the links between sleep and dementia. While we know that people with Alzheimer's experience disturbed sleep patterns, whether this contributes to the disease or is an early consequence has been unclear. This study observes changes in daily rest and activity patterns at an early stage, where people are showing signs of Alzheimer's in the brain but before symptoms begin.
"In the past, studies have used sleep diaries to look at the links between sleep and health conditions, but the development of wearable activity monitors is helping researchers gain deeper and more accurate insight into the factors at play. We can't conclude from this study that napping more during the day can lead to dementia, and future studies will need to follow volunteers over longer periods of time. Studies like this add new pieces to the jigsaw of our understanding, and could lay the groundwork for new ways to detect the condition earlier, focusing on a range of factors and not just memory and thinking tests."


Provided by Alzheimer's Research UK

Meditation and music may help reverse early memory loss in adults at risk for Alzheimer's disease

In a recent study of adults with early memory loss, a West Virginia University research team lead by Dr. Kim Innes found that practice of a simple meditation or music listening program may have multiple benefits for older adults with preclinical memory loss.

25 jan 2017--In this randomized controlled trial, 60 older adults with subjective cognitive decline (SCD), a condition that may represent a preclinical stage of Alzheimer's disease, were assigned to either a beginner meditation (Kirtan Kriya) or music listening program and asked to practice 12 minutes/day for 12 weeks. As detailed in a paper recently published by the Journal of Alzheimer's Disease, both the meditation and music groups showed marked and significant improvements in subjective memory function and objective cognitive performance at 3 months. These included domains of cognitive functioning most likely to be affected in preclinical and early stages of dementia (e.g., attention, executive function, processing speed, and subjective memory function). The substantial gains observed in memory and cognition were maintained or further increased at 6 months (3 months post-intervention).
As explained in the research team's previous paper (J Alzheimer's Dis. 52 (4): 1277-1298), both intervention groups also showed improvements in sleep, mood, stress, well-being and quality of life, with gains that were that were particularly pronounced in the meditation group; again, all benefits were sustained or further enhanced at 3 months post-intervention.
The findings of this trial suggest that two simple mind-body practices, Kirtan Kriya meditation and music listening, may not only improve mood, sleep, and quality of life, but also boost cognition and help reverse perceived memory loss in older adults with SCD.

More information: Kim E. Innes et al. Meditation and Music Improve Memory and Cognitive Function in Adults with Subjective Cognitive Decline: A Pilot Randomized Controlled Trial, Journal of Alzheimer's Disease (2017). DOI: 10.3233/JAD-160867


Provided by IOS Press

Landmark editorial identifies microbes as major cause of Alzheimer's disease

A worldwide team of senior scientists and clinicians have come together to produce an editorial which indicates that certain microbes - a specific virus and two specific types of bacteria—are major causes of Alzheimer's disease. Their paper, which has been published online in the highly regarded peer-reviewed journal, Journal of Alzheimer's disease, stresses the urgent need for further research—and more importantly, for clinical trials of anti-microbial and related agents to treat the disease.

09 mar 2016--This major call for action is based on substantial published evidence and research into Alzheimer's. The team's landmark editorial summarises the abundant data implicating these microbes, but until now this work has been largely ignored or dismissed as controversial—despite the absence of evidence to the contrary. Therefore, proposals for the funding of clinical trials have been refused, despite the fact that over 400 unsuccessful clinical trials for Alzheimer's based on other concepts were carried out over a recent 10-year period.
Opposition to the microbial concepts resembles the fierce resistance to studies some years ago which showed that viruses cause certain types of cancer, and that a bacterium causes stomach ulcers. Those concepts were ultimately proved valid, leading to successful clinical trials and the subsequent development of appropriate treatments.
Professor Douglas Kell of The University of Manchester's School of Chemistry and Manchester Institute of Biotechnology is one of the editorial's authors. He says that supposedly sterile red blood cells were seen to contain dormant microbes, which also has implications for blood transfusions. "We are saying there is incontrovertible evidence that Alzheimer's disease has a dormant microbial component, and that this can be woken up by iron dysregulation. Removing this iron will slow down or prevent cognitive degeneration – we can't keep ignoring all of the evidence."
Professor Resia Pretorius of the University of Pretoria, who worked with Douglas Kell on the editorial, said "The microbial presence in blood may also play a fundamental role as causative agent of systemic inflammation, which is a characteristic of Alzheimer's disease—particularly, the bacterial cell wall component and endotoxin, lipopolysaccharide. Furthermore, there is ample evidence that this can cause neuroinflammation and amyloid-β plaque formation."
The findings of this editorial could also have implications for the future treatment of Parkinson's disease, and other progressive neurological conditions.


Provided by University of Manchester

Study finds cerebrovascular disease to be major determinant of psychosis in patients with Alzheimer's

Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

About half of all patients with Alzheimer's disease develop symptoms of psychosis, such as delusions or hallucinations.
But the pathological mechanisms that underlie psychotic symptoms are unclear, limiting the ability to manage and treat them. Some studies have suggested they are related to the underlying causes of Alzheimer's disease such as the protein deposits found in the brains of Alzheimer's patients, but others found no correlation.

06 jan2016--A study published today in the Journal of Alzheimer's Disease found that cerebrovascular disease is a major determinant of psychosis in people with Alzheimer's disease. Cerebrovascular disease is a group of conditions that restrict the circulation of blood to the brain.
Using data from the National Alzheimer's Coordinating Centre database collected from 29 Alzheimer's disease centres in the United States between 2005 and 2012, researchers led by Dr. Corinne Fischer, a psychiatrist and researcher at St. Michael's Hospital, analyzed autopsy data from 1,073 people.
Of the 890 people who had been clinically diagnosed with Alzheimer's while they were alive, the people most likely to be psychotic were those whose autopsies showed they had more physical signs of Alzheimer's such as neuritic plaques (protein deposits) and neurofibrillary tangles (twisted fibers found inside brain cells).
But when they looked at the 728 people whose autopsies confirmed they had Alzheimer's, those with psychosis did not show increased physical evidence of Alzheimer's disease. Alzheimer's can only be confirmed through an autopsy, so some patients in the clinically diagnosed group had been misdiagnosed with Alzheimer's.
In both groups of patients, psychosis correlated significantly with Lewy bodies, abnormal protein aggregates found in nerve cells of patients with Parkinson's disease. This was not an unexpected finding since psychosis is prominent when dementia accompanies Parkinson's disease.
What was entirely unexpected was the prominent role in psychosis of vascular risk factors (hypertension, diabetes, age at quitting smoking) and cerebral injuries related to small vessel disease,
About 19 per cent of people with Alzheimer's who live in the community (rather than in institutions) are thought to have delusions and 14 per cent have hallucinations. Psychotic symptoms are significant in Alzheimer's patients because they have been shown to be associated with increased burden on caregivers, increased functional decline and more rapid progression of the disease.


Provided by St. Michael's Hospital

Scientists isolate genes that delay Alzheimer's

Associate Professor Arcos-Burgos (centre) with Dr Claudio Mastronardi and Dr Hardip Patel. Credit: Stuart Hay, ANU

Scientists have identified a network of nine genes that play a key role in the onset of Alzheimer's Disease.

02 dec 2915--The finding could help scientists develop new treatments to delay the onset of the disease, said lead researcher Associate Professor Mauricio Arcos-Burgos from The Australian National University (ANU).
In a study of a family of 5,000 people in Columbia, scientists identified genes that delayed the disease, and others that accelerated it, and by how much.
"If you can work out how to decelerate the disease, then you can have a profound impact," said Associate Professor Arcos-Burgos, a medical geneticist at The John Curtin School of Medical Research (JCSMR) at ANU.
"I think it will be more successful to delay the onset of the disease than to prevent it completely. Even if we delay the onset by on average one year, that will mean nine million fewer people have the disease in 2050."
Alzheimer's disease affects up to 35 million people around the world and is predicted to affect one in 85 people globally by 2050.
The Columbian family are afflicted by a type of hereditary Alzheimer's. They are a unique resource in the fight against the disease because they are such a large, close-knit family and live in a specific region in the western mountains of Columbia.
The United States National Institute of Health has put $170 million towards developing treatments for Alzheimer's, which will be tested amongst this family.
Associate Professor Arcos-Burgos and his team took a different approach, studying the variable age of onset of dementia in this family, rather than trying to treat symptoms which develop later in life, even though changes in the brain can be observed in individuals before the age of 20.
With the cooperation of the family, the team were able to discount environmental factors and trace their genetic predisposition to Alzheimer's Disease back to a founder mutation in one individual who came to the region about 500 years ago.
The team was able to isolate the nine genes involved in Alzheimer's, some of which delay the onset by up to 17 years, while others advance its progress.
Associate Professor Arcos-Burgos is now turning closer to home, to study the genes of a group of Queanbeyan people who have been followed for the past 10 years.
The study is published in Molecular Psychiatry.

More information: J I Vélez et al. APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease, Molecular Psychiatry (2015). DOI: 10.1038/mp.2015.177


Provided by Australian National University

Alzheimer's patients' health care costs higher already before diagnosis

Diagram of the brain of a person with Alzheimer's Disease. 

The health care costs of patients diagnosed with Alzheimer's disease (AD) start to increase already one year before the diagnosis, shows a new study from the University of Eastern Finland.

18 nov 2015--The differences in the health care costs between AD patients and non-AD patients were the greatest during six months following the diagnosis, with AD patients having 5,088 euros higher health care costs per person-year. After the first six months, the differences evened out. Two years after the diagnosis, the health care costs of AD patients stabilised at a level two times higher than that of non-AD patients.
The majority of the health care costs of AD patients, i.e. 78-84 per cent, were caused by hospital care and only a fraction by drug therapy. Anti-dementia drugs initiated after the diagnosis explained the majority of the drug costs. Five years prior to the diagnosis, Alzheimer's patients had on average 1.4 hospital days more per person-year than non-AD patients, whereas two years after the diagnosis they had as many as 14.2 hospital days more.
The study used data from the Finnish Medication Use and Alzheimer's Disease Study, Medalz, and analysed the hospital care and drugs costs of 70,718 Finnish AD patients living in their own home and the hospital care and drug costs of as many non-AD patients from five years before until two years after the diagnosis.
Data of AD diagnoses was obtained from the Finnish Social Insurance Institution's Reimbursement Register, data on hospital days from the Finnish Hospital Discharge Register, and data on medication from the Finnish Social Insurance Institution's Prescription Register. The costs of drug therapy were analysed as overall costs, and the costs of hospital days were calculated according to the Finnish health care system's unit costs, which also include the patient's payment contribution.

More information: Hospital care and drug costs from 5 years before until 2 years after the diagnosis of Alzheimer's disease in a Finnish nationwide cohort. Heidi Taipale, Maija Purhonen, Anna-Maija Tolppanen, Antti Tanskanen, Jari Tiihonen, Sirpa Hartikainen. Scandinavian Journal of Public Health, published online 9.11.2015. sjp.sagepub.com/content/early/2015/11/04/1403494815614705.abstract


Provided by University of Eastern Finland

Study shows poor heart function could be major risk for Alzheimer's disease

Heart diagram. Credit: Wikipedia

A healthier heart could prevent Alzheimer's disease, according to new research at Vanderbilt University Medical Center.

08 mar 2015--The study, published online Feb. 19 in Circulation, associates heart function with the development of dementia and Alzheimer's disease. Participants with decreased heart function, measured by cardiac index, were two to three times more likely to develop significant memory loss over the follow-up period.

"Heart function could prove to be a major risk factor for dementia and Alzheimer's disease," said Angela Jefferson, Ph.D., director of the Vanderbilt Memory & Alzheimer's Center, and principal investigator of the study.

"A very encouraging aspect of our findings is that heart health is a modifiable risk. You may not be able to change your genetics or family history, but you can engage in a heart healthy lifestyle through diet and exercise at any point in your lifetime."

The research used data from the Framingham Heart Study, an effort that began in 1948 to identify risk factors for heart disease. 1,039 participants from Framingham's Offspring Cohort were followed for up to 11 years to compare cardiac index to the development of dementia.

"Cardiac index is a measure of heart health. It reflects cardiac output or the amount of blood that leaves the heart and is pumped through the body taking into consideration a person's body size. A low cardiac index value means there is less blood leaving the heart," Jefferson said.

Over the study period, 32 participants developed dementia, including 26 cases of Alzheimer's disease. Compared to normal cardiac index, individuals with clinically low cardiac index had a higher relative risk of dementia.

"We thought heart disease might be driving the increased risk of dementia and Alzheimer's disease. When we excluded participants with heart disease and other heart conditions, we were surprised that the risk of dementia and Alzheimer's disease got even worse," Jefferson said.

Jefferson said the research community has long associated heart health with brain health, but cardiac index has not been previously recognized as a risk factor for significant memory loss or dementia.

"For the average adult, the brain accounts for 2 percent of overall body weight but receives as much as 15 percent of blood leaving the heart. If there are changes in the heart's ability to pump blood, the brain is resilient and does a great job at regulating blood flow to maintain a consistent level to support brain tissue and activity. But as we age, our vessels tend to be less healthy. They become less adaptable to blood flow changes, and those changes may affect brain health and function," she said.

"The risk we found between lower cardiac index and the development of dementia may reflect a subtle but protracted process that occurs over decades —essentially a lifetime burden of subtle reductions in oxygen and nutrient delivery to the brain. That possibility is concerning given the observation that one in three participants in our study met the medical definition for low cardiac index."

Jefferson emphasizes that this research points only to a risk factor.

"At present, there is no proven method for preventing dementia or Alzheimer's disease. But leading a heart healthy lifestyle could help. When 30 percent of the population is exposed to a potential risk factor, like low cardiac index, that suggests it may be of significant public health concern."

Provided by Vanderbilt University Medical Center

Skin test may shed new light on Alzheimer's and Parkinson's diseases

Scientists have discovered a skin test that may shed new light on Alzheimer's and Parkinson's diseases, according to a study released today will be presented at the American Academy of Neurology's 67th Annual Meeting in Washington, D.C., April 18 to 25, 2015.

27 feb 2015--The study showed that skin biopsies can be used to detect elevated levels of abnormal proteins found in the two diseases.

"Until now, pathological confirmation was not possible without a brain biopsy, so these diseases often go unrecognized until after the disease has progressed," said study author Ildefonso Rodriguez-Leyva, MD, at Central Hospital at the University of San Luis Potosi in San Luis Potosi, Mexico. "We hypothesized that since skin has the same origin as brain tissue while in the embryo that they might also show the same abnormal proteins. This new test offers a potential biomarker that may allow doctors to identify and diagnose these diseases earlier on."

For the study, researchers took skin biopsies from 20 people with Alzheimer's disease, 16 with Parkinson's disease and 17 with dementia caused by other conditions and compared them to 12 healthy people in the same age group. They tested these skin samples to see if specific types of altered proteins were found—ones that indicate a person has Alzheimer's or Parkinson's.

As compared to healthy patients and ones with dementia caused by other conditions, those with both Alzheimer's and Parkinson's had seven times higher levels of the tau protein. People with Parkinson's also had an eight times higher level of alpha-synuclein protein than the healthy control group.

Alzheimer's disease is ranked as the sixth leading cause of death in the United States, and 5.4 million Americans are currently diagnosed with Alzheimer's disease. Parkinson's disease affects one million Americans, with at least 60,000 new cases reported annually each year.

"More research is needed to confirm these results, but the findings are exciting because we could potentially begin to use skin biopsies from living patients to study and learn more about these diseases. This also means tissue will be much more readily available for scientists to study," said Rodriguez-Leyva. "This procedure could be used to study not only Alzheimer's and Parkinson's, but also other neurodegenerative diseases."

Provided by American Academy of Neurology

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.

Key cellular auto-cleaning mechanism mediates the formation of plaques in Alzheimer's brain

Aβ plaque formation depends on autophagy. Immunohistological analysis of Aβ plaque of 20-month-old APP and Atg7flox/flox; CamKII-Cre x APP mouse brains. Credit: Per Nilsson, RIKEN

Autophagy, a key cellular auto-cleaning mechanism, mediates the formation of amyloid beta plaques, one of the hallmarks of Alzheimer's disease. It might be a potential drug target for the treatment of the disease, concludes new research from the RIKEN Brain Science Institute in Japan. The study sheds light on the metabolism of amyloid beta, and its role in neurodegeneration and memory loss.

06 oct 2013--In a study published today in the journal Cell Reports, Drs. Per Nilsson, Takaomi Saido and their team show for the first time using transgenic mice that a lack of autophagy in neurons prevents the secretion of amyloid beta and the formation of amyloid beta plaques in the brain. The study also reveals that an accumulation of amyloid beta inside neurons is toxic for the cells.

Alzheimer's disease, the most common form of dementia, affects nearly 36 million people worldwide, and this number is set to double over the next 20 years. However, the causes of the disease are not well understood and no disease-modifying treatment is available today.

Patients with Alzheimer's disease have elevated levels of the peptide amyloid beta in their brain and amyloid beta plaques form outside their neurons. This accumulation of amyloid beta causes the neurons to die, but until now the underlying mechanism remained a mystery. And whether the elevated levels of the peptide inside or outside the cells are to blame was unknown.

Autophagy is a cellular cleaning mechanism that normally clears any protein aggregates or other 'trash' within the cells, but that is somewhat disturbed in Alzheimer's patients.

Autophagy mediates Aβ secretion. wt and autophagy-deficient Atg7flox/flox; Nes-Cre primary neurons expressing APP were stained for Aβ. Credit: Per Nilsson, RIKEN

To investigate the role of autophagy in amyloid beta metabolism, Nilsson et al. deleted an important gene for autophagy, Atg7, in a mouse model of Alzheimer's disease. Contrary to what they were expecting, their results showed that a complete lack of autophagy within neurons prevents the formation of amyloid beta plaque around/outside the cells. Instead, the peptide accumulates inside the neurons, where it causes neuronal death, which in turn leads to memory loss.

This is a graphical overview depicting the role of autophagy in Aβ secretion from neurons. Credit: Per Nilsson, RIKEN

"Our study explains how amyloid beta is secreted from the neurons, via autophagy, which wasn't well understood," comments Dr Nilsson. "To control amyloid beta metabolism including its secretion is a key to control the disease. Autophagy might therefore be a potential drug target for the treatment of Alzheimer's disease," he adds.

More information: Nilsson et al., "Ab Secretion and Plaque Formation Depend on Autophagy" Cell Reports (2013) DOI: 10.1016/j.celrep.2013.08.042

Provided by RIKEN

Scientists reveal how beta-amyloid may cause Alzheimer's

Artist rendering of β-amyloid oligomers (red) and receptor LilrB2 or PirB (green) in neuronal synapses of Alzheimer’s brains. Inhibitory immune receptors LilrB2 in human brain and its murine ortholog PirB were discovered to act as neuronal receptors for β-amyloid oligomers, which contribute to synaptic dysfunction and memory defects in Alzheimer’s disease. Credit: Eric Smith, Carla Shatz, and Taeho Kim

Scientists at the Stanford University School of Medicine have shown how a protein fragment known as beta-amyloid, strongly implicated in Alzheimer's disease, begins destroying synapses before it clumps into plaques that lead to nerve cell death.

21 sept 2013--Key features of Alzheimer's, which affects about 5 million Americans, are wholesale loss of synapses—contact points via which nerve cells relay signals to one another—and a parallel deterioration in brain function, notably in the ability to remember.

"Our discovery suggests that Alzheimer's disease starts to manifest long before plaque formation becomes evident," said Carla Shatz, PhD, professor of neurobiology and of biology and senior author of a study that will be published Sept. 20 in Science.

Investigators at Harvard University also contributed to the study. The research, conducted in mice and in human brain tissue, may help to explain the failures in recent years of large-scale clinical trials attempting to slow the progression of Alzheimer's by pharmacologically ridding the brain of amyloid plaques. It may also point the way to better treatments at earlier stages of the disease.

Beta-amyloid begins life as a solitary molecule but tends to bunch up—initially into small clusters that are still soluble and can travel freely in the brain, and finally into the plaques that are hallmarks of Alzheimer's. The study showed for the first time that in this clustered form, beta-amyloid can bind strongly to a receptor on nerve cells, setting in motion an intercellular process that erodes their synapses with other nerve cells.

Synapses are the connections between nerve cells. They are essential to storing memories, processing thoughts and emotions, and planning and ordering how we move our bodies. The relative strength of these connections, moreover, can change in response to new experiences.

Using an experimental mouse strain that is highly susceptible to the synaptic and cognitive impairments of Alzheimer's disease, Shatz and her colleagues showed that if these mice lacked a surface protein ordinarily situated very close to synapses, they were resistant to the memory breakdown and synapse loss associated with the disorder. The study demonstrated for the first time that this protein, called PirB, is a high-affinity receptor for beta-amyloid in its "soluble cluster" form, meaning that soluble beta-amyloid clusters stick to PirB quite powerfully. That trips off a cascade of biochemical activities culminating in the destruction of synapses.

Shatz is the Sapp Family Provostial Professor, as well as the director of Bio-X, a large Stanford interdisciplinary consortium drawing on medical, engineering and biology faculty. She has been studying PirB for many years, but in a different context. In earlier work, Shatz explored the role of PirB in the brain using genetically engineered mice that lacked it. She discovered that PirB, previously thought to be used only by cells in the immune system, is also found on nerve cells in the brain, where it slows the ability of synapses to strengthen in proportion to the extent to which they are engaged, and actually promotes their weakening. Such brakes are desirable in the brain because too-easy synaptic strength-shifting could trigger untoward consequences like epilepsy.

In the new study, Shatz's team employed a different genetically engineered mouse strain whose genome contained mutant copies of two separate human genes. Each of these mutations is known to predispose individuals to Alzheimer's disease. When both mutations are present in mice, which ordinarily never develop amyloid plaques, the result is abundant amyloid plaque deposition with advancing age, as well as an eventual decline in performance on various tests of memory.

PirB (red) is heavily concentrated on the surface of growing nerve cells. Credit: Dr. Carla Shatz, Stanford University.

"I've always found it strange that these mice—and, in fact, all the mouse models for Alzheimer's disease that we and other people study—seem not to have any problems with memory until they get old," Shatz said. "These mice's brains have high levels of beta-amyloid at a very early age."

Shatz found herself wondering if there might be a more sensitive measure of beta-amyloid's early effects on young brains. A study she co-authored in 2012 demonstrated that a particular mouse brain region, whose constituent synapses are normally quite nimble at shifting their relative strengths in response to early-life experiences, showed no such flexibility in young Alzheimer's-prone mice. This suggested that subtle Alzheimer's-related effects might appear far earlier than plaques or memory loss do.

Now, Shatz wondered whether eliminating PirB from the Alzheimer's mouse strain could restore that flexibility. So her team bred the Alzheimer's-genes-carrying strain with the PirB-lacking strain to create hybrids. Experimentation showed that the brains of young "Alzheimer's mice" in which PirB was absent retained as much synaptic-strength-shifting flexibility as those of normal mice. PirB-lacking Alzheimer's mice also performed as well in adulthood as normal mice did on well-established tests of memory, while their otherwise identical PirB-expressing peers suffered substantial synapse and memory loss.

"The PirB-lacking Alzheimer's mice were protected from the beta-amyloid-generating consequences of their mutations," Shatz said. The question now was, why?

Taeho Kim, PhD, a postdoctoral scholar in Shatz's lab and the lead author of the new study, advanced a hypothesis he had cooked up in 2011 while describing his research to a captive audience of one—his then-4-year-old son, whom he was driving to the Monterey Bay Aquarium: Maybe PirB and beta-amyloid were binding. This might cause PirB to stomp on the brakes even more than it usually does, weakening synapses so much they could disappear altogether, taking memories with them.

Further experiments showed that, indeed, beta-amyloid binds strongly to PirB. While PirB is specifically a mouse protein, Kim also identified for the first time an analogous beta-amyloid receptor in the human brain: a protein called LilrB2.

In another experiment, Kim compared proteins in the brains of PirB-lacking Alzheimer's mice to those in the brains of PirB-expressing Alzheimer's mice. The latter showed significantly increased activity on the part of a few workhorse proteins, notably an enzyme called cofilin. Subsequent studies also found that cofilin activity in the brains of autopsied Alzheimer's patients is substantially higher than in the brains of people without the disorder.

Here the plot thickens: Cofilin works by breaking down actin, a building-block protein essential to maintaining synaptic structure. And, as the new study also showed, beta-amyloid's binding to PirB results in biochemical changes to cofilin that revs up its actin-busting, synapse-disassembling activity.

"No actin, no synapse," Shatz said.

Kim's hypothesis appears to have been correct. Beta-amyloid binds to PirB (and, the researchers proved, to its human analog, LilrB2), boosting cofilin activity and busting synapses' structural integrity.

Although there may be other avenues of destruction along which synapses are forced to walk, Shatz doubts there are very many. She said she thinks the direct participation of beta-amyloid—as well as cofilin, so clearly implicated in synaptic breakdown—suggests that this pathway is important. "We looked at human brains in this study, too, and we found that a similar derangement of cofilin activity is present in Alzheimer's brains but not healthy brains," she said.

Shatz suggested that drugs that block beta-amyloid's binding to PirB on nerve-cell surfaces—for example, soluble PirB fragments containing portions of the molecule that could act as decoy—might be able to exert a therapeutic effect. "I hope this finding will be enticing enough to pharmaceutical and biotechnology companies that someone will try pushing this idea forward," she said.

More information: Human LilrB2 Is a beta-Amyloid Receptor and Its Murine Homolog PirB Regulates Synaptic Plasticity in an Alzheimer's Model," by T. Kim et al. Science, 2013. DOI: 10.1126/science.1242077

Provided by Stanford University Medical Center