Abstract
Delirium increases the risk of developing new dementia 8-fold in older patients
Delirium also found to worsen severity in those already diagnosed with dementia and increase the pace of cognitive decline
Older people who have experienced episodes of delirium are significantly more likely to develop dementia, according to new research. The study is published in the journal Brain today, Thursday, 09August.
When in hospital, older people sometimes become acutely confused and disorientated. This condition, known as delirium, affects at least 15 per cent of older people in hospitals and has long thought to be simply a temporary side effect of other illness (such as an infection, a reaction to a medication or an operation). However, the new research shows that episodes of delirium can have long term effects - increasing the future risk of dementia eight-fold.
Dr Daniel Davis, lead author of the paper from the University of Cambridge, said: “This means that delirium, or the acute causes of delirium, could be a newly discovered cause of dementia. This is important, because although delirium is extremely common, less than a quarter of cases are actually diagnosed in hospitals.”
Scientists at the University of Cambridge and the University of Eastern Finland recruited 553 people aged 85 and over, and assessed their memory and thinking over 10 years. Of the patients who had previously experienced at least one episode of delirium prior to the study, 77 per cent also had dementia. In comparison, only 33 per cent of the patients who had no previous history of delirium had dementia. They also recorded the number of episodes of delirium throughout the study.
In people without pre-existing dementia, experiencing delirium resulted in an eight-fold increase in the risk of dementia. In individuals with existing dementia, delirium was associated with an acceleration of dementia severity, loss of independence in physical functioning, and higher mortality.
Dr Davis added: “Worsening confusion and disorientation in older persons does not attract much attention among clinical staff and many believe that delirium is simply an inconvenient consequence of illness. However, this research suggests the possibility that delirium, or the problems giving rise to delirium, may be actually causing brain damage.
“Because some delirium is preventable, it is plausible that delirium prevention may lead to dementia prevention. We now urgently need to test if better delirium care can prevent dementia, or prevent further decline in patients who already have dementia.”
The Wellcome Trust-funded study also found, for the first time, that there may be differences in the brains of people who have had delirium compared to those without delirium. Dementia is known to result from a several different pathological processes (e.g. accumulation of abnormal proteins, or blockages in blood vessels). However, this study found that when individuals had both delirium and dementia, these standard neuropathological markers were not enough to explain the dementia. This raises the important possibility that dementia occurring after delirium had alternative pathological processes causing the dementia.
Professor Clive Ballard, Director of Research at Alzheimer's Society, said: “Scientists have believed there could be a link between delirium and dementia for many years. This robust study adds weight to this knowledge. With hospitalisation thought to be a cause of delirium, it's vital that healthcare professionals recognise the potential long term impact of delirium and are aware that older people who experience episodes could be susceptible to developing dementia.”
Dr Karin Neufeld, President-Elect of the American Delirium Society and Director of General Hospital Psychiatry at Johns Hopkins Hospital, commented: “Research on delirium has repeatedly highlighted the association between cognitive impairment, and dementia and the development of delirium in the hospital setting in elderly individuals.
“This important research suggests that preventing delirium might be an important way to decrease the onset and progression of dementia in some people. The implication is that we, as healthcare professionals, need to redouble our efforts to detect and prevent delirium in hospitalised patients.” (Source: EurekAlert! A service of AAAS and University of Cambridge).
Anti-tau drug improves cognition, decreases tau tangles in Alzheimer's disease models
Drugmaker begins phase i clinical trial to test microtubule stabilizing-drug in mild Alzheimer's cases
VANCOUVER - While clinical trial results are being released regarding drugs intended to decrease amyloid production - thought to contribute to decline in Alzheimer's disease - clinical trials of drugs targeting other disease proteins, such as tau, are in their initial phases.
Penn Medicine research presented today at the 2012 Alzheimer's Association International Conference (AAIC) shows that an anti-tau treatment called epithilone D (EpoD) was effective in preventing and intervening the progress of Alzheimer's disease in animal models, improving neuron function and cognition, as well as decreasing tau pathology.
By targeting tau, the drug aims to stabilize microtubules, which help support and transport of essential nutrients and information between cells. When tau malfunctions, microtubules break and tau accumulates into tangles.
“This drug effectively hits a tau target by correcting tau loss of function, thereby stabilizing microtubules and offsetting the loss of tau due to its formation into neurofibrillary tangles in animal models, which suggests that this could be an important option to mediate tau function in Alzheimer's and other tau-based neurodegenerative diseases,” said John Trojanowski, MD, PhD, professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania.“In addition to drugs targeting amyloid, which may not work in advanced Alzheimer's disease, our hope is that this and other anti-tau drugs can be tested in people with Alzheimer's disease to determine whether stabilizing microtubules damaged by malfunctioning tau protein may improve clinical and pathological outcomes.”
The drug, identified through Penn's Center for Neurodegenerative Disease Research (CNDR) Drug Discovery Program, was previously shown to prevent further neurological damage and improve cognitive performance in animal models*. The Penn research team includes senior investigator Bin Zhang, MD, and Kurt Brunden, PhD, director of Drug Discovery at CNDR. (Source: EurekAlert! A service of AAAS and University of Pennsylvania School of Medicine).
Study examines effects of growth hormone-releasing hormone on cognitive function
CHICAGO – Treatment with growth hormone-releasing hormone appears to be associated with favorable cognitive effects among both adults with mild cognitive impairment and healthy older adults, according to a randomized clinical trial published Online First by Archives of Neurology, a JAMA Network publication.
“Growth hormone-releasing hormone (GHRH), growth hormone and insulinlike growth factor 1 have potent effects on brain function, their levels decrease with advancing age, and they likely play a role in the pathogenesis of Alzheimer disease,” the authors write as background information in the study.
To examine the effects of GHRH on cognitive function in healthy older adults and in adults with mild cognitive impairment (MCI), Laura D. Baker, Ph.D., of the University of Washington School of Medicine and Veterans Affairs Puget Sound Health Care System, Seattle, and colleagues, conducted a randomized, double-blind, placebo-controlled trial in which participants self-administered daily injections of a form of human GHRH (tesamorelin), or placebo.
The authors enrolled 152 adults ranging in age from 55 to 87 years (average age, 68 years) and 137 participants (76 healthy patients and 61 patients with MCI) successfully completed the study. At baseline, at 10 and 20 weeks of treatment, and after a 10-week washout (30 weeks total), the authors collected blood samples and administered parallel versions of cognitive tests.
Among the original 152 patients enrolled in the study, analysis indicated a favorable effect of GHRH on cognition, which was comparable in adults with MCI and healthy older adults. Analysis among the 137 patients who successfully completed the trial also showed that treatment with GHRH had a favorable effect on cognition among both groups of patients. Although the healthy adults outperformed those with MCI overall, the cognitive benefits relative to placebo was comparable among both groups.
Treatment with GHRH also increased insulinlike growth factor 1 levels by 117 percent, which remained within the physiological range, and increased fasting insulin levels within the normal range by 35 percent in adults with MCI but not in healthy adults.
“Our results replicate and expand our earlier positive findings, demonstrating that GHRH administration has favorable effects on cognitive function not only in healthy older adults but also in adults at increased risk of cognitive decline and dementia,” the authors conclude.“Larger and longer-duration treatment trials are needed to firmly establish the therapeutic potential of GHRH administration to promote brain health in normal aging and ‘pathological aging.’”(Source: EurekAlert! A service of AAAS and JAMA and Archives Journals).
Binge drinking increases the risk of cognitive decline in older adults
Researchers from the Peninsula College of Medicine and Dentistry (PCMD), University of Exeter, will present the findings of a new study suggesting a link between binge drinking in older adults and the risk of developing dementia.
The findings are to be presented at the Alzheimer's Association International Conference 2012, the world's largest gathering of dementia researchers, in Vancouver, Canada on 18th July 2012. The work is supported by the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care in the South West Peninsula (NIHR PenCLAHRC).
Little is known about the cognitive effects of binge drinking in older people, which led the PCMD research team to investigate. Dr. Iain Lang from PCMD, who led the study, said: “We know binge drinking can be harmful: it can increase the risk of harm to the cardiovascular system, including the chance of developing heart disease; and it is related to an increased risk of both intentional and unintentional injuries. However, until we conducted our study it was not clear what the effect was of binge drinking on cognitive function and the risk of developing dementia.”
The research team analysed data from 5,075 participants aged 65 and older in the Health and Retirement Study (HRS), a biennial, longitudinal, nationally representative survey of U.S. adults, to assess the effects of binge drinking in older people on their function. Initial data were collected in 2002 and participants were followed for eight years. Consumption of four or more drinks on one occasion was considered binge drinking. Cognitive function and memory were assessed using the Telephone Interview for Cognitive Status.
The research showed binge drinking once a month or more was reported by 8.3 per cent of men and 1.5 per cent of women; binge drinking twice a month or more was reported by 4.3 per cent of men and 0.5 per cent of women.
The researchers found that: participants who reported binge drinking at least once a month were 62% more likely to be in the group experiencing the greatest 10% of decline in cognitive function, and 27% more likely to be in the group experiencing the greatest 10% of memory decline. participants reporting heavy episodic drinking twice a month or more were two-and-a-half times more likely to be in the group experiencing the greatest 10 per cent of decline in cognitive function and also two-and-a-half times more likely to be in the group experiencing the greatest 10% of decline in memory.
Outcomes were similar in men and women.
“In our group of community-dwelling older adults, binge drinking is associated with an increased risk of cognitive decline,” said Dr. Lang. “That's a real worry because there's a proven link between cognitive decline and risk of dementia. Those who reported binge drinking at least twice a month were more than twice as likely to have higher levels of decline in both cognitive function and memory. These differences were present even when we took into account other factors known to be related to cognitive decline such as age and level of education.”
He added: “This research has a number of implications. First, older people – and their doctors – should be aware that binge drinking may increase their risk of experiencing cognitive decline and encouraged to change their drinking behaviours accordingly. Second, policymakers and public health specialists should know that binge drinking is not just a problem among adolescents and younger adults. We have to start thinking about older people when we are planning interventions to reduce binge drinking.” (Source: EurekAlert! A service of AAAS and The Peninsula College of Medicine and Dentistry).
Alzheimer's plaques in PET brain scans identify future cognitive decline
DURHAM, N.C. – Among patients with mild or no cognitive impairment, brain scans using a new radioactive dye can detect early evidence of Alzheimer's disease that may predict future decline, according to a multi-center study led by researchers at Duke University Medical Center.
The finding is published online July 11, 2012, in the journal Neurology, the medical journal of the American Academy of Neurology. It expands on smaller studies demonstrating that early detection of tell-tale plaques could be a predictive tool to help guide care and treatment decisions for patients with Alzheimer's disease.
“Even at a short follow-up of 18 months we can see how the presence of amyloid plaques affects cognitive function,” said P. Murali Doraiswamy, M.D., professor of psychiatry at Duke who co-led the study with R. Edward Coleman, M.D., professor of radiology at Duke .“Most people who come to the doctor with mild impairment really want to know the short-term prognosis and potential long-term effect.”
Doraiswamy said such knowledge also has some pitfalls. There is no cure for Alzheimer's disease, which afflicts 5.4 million people in the United States and is the sixth-leading cause of death among U.S. adults. But he said numerous drugs are being investigated, and identifying earlier disease would improve research into their potential benefits and speed new discoveries, while also enhancing care and treatment of current patients.
In the Neurology study, 151 people who had enrolled in a multi-center test of a new radioactive dye called florbetapir (Amyvid) were recruited to participate in a 36-month analysis. Of those participants, 69 had normal cognitive function at the start of the study, 51 had been diagnosed with mild impairment, and 31 had Alzheimer's dementia.
All completed cognitive tests and underwent a brain scan using Positron Emission Tomography, or PET imaging. The technology uses radioactive tracers designed to highlight specific tissue to create a three-dimensional picture of an organ or a biological function.
The dye used in the study, florbetapir, was recently approved by the U.S. Food and Drug Administration for PET imaging of the brain to estimate beta-amyloid plaque density in patients who are being evaluated for cognitive impairment. It binds to the amyloid plaques that characterize Alzheimer's disease, providing a window into the brain to see if the plaques have formed, and how extensively.
Patients in the study were reassessed with additional cognitive exams at 18 months and 36 months. At the 18-month point, patients with mild cognitive impairment who had PET evidence of plaque at the trial's start worsened to a great degree on cognitive tests than patients who had no evidence of plaque at the trial's start. Twenty-nine percent of the plaque-positive patients in this group developed Alzheimer's dementia, compared to 10 percent who started with no plaque.
Cognitively normal patients with a plaque-positive PET scan at the start of the study also showed more mental decline at 18 months compared to those who were negative for plaque.
The study additionally found that people with negative scans reversed from minimally impaired to normal more often than people with positive PET scan, suggesting test anxiety or concentration problems could have affected their initial performance.
“For the most part we have been blind about who would progress and who wouldn't, so this approach is a step toward having a biomarker that predicts risk of decline in people who are experiencing cognitive impairment,” Doraiswamy said.
He said the study's results provide initial data that needs to be verified by additional research. Final, 36-month data from the study has been completed and will be presented at the Alzheimer's Association International Conference this week in Vancouver, Canada. Doraiswamy also cautioned that florbetapir is currently not approved to predict the development of dementia or other neurologic conditions and stressed that it should not be used as a screening tool in otherwise normal or minimally impaired people. Likewise, a positive scan is not necessarily diagnostic for Alzheimer's by itself. (Source: EurekAlert! A service of AAAS and Duke University Medical Center).
Postoperative delirium in cardiac surgery patients associated with prolonged cognitive impairment
Preventing postoperative delirium may improve recovery of cognitive ability in cardiac patients
WORCESTER, MA –Older patients undergoing cardiac surgery often experience changes in cognitive function, such as memory problems or an inability to focus, in the days immediately following their operations. While these changes are usually temporary, for unknown reasons, a significant number of cardiac patients will encounter long-term cognitive problems, lasting as long as a year after their surgeries.
Now, new research published in the July 5 issue of The New England Journal of Medicine (NEJM), establishes a link between postoperative delirium and prolonged loss of cognitive function in cardiac surgery patients. Led by investigators at the University of Massachusetts Medical School, Beth Israel Deaconess Medical Center and the Aging Brain Center at Hebrew SeniorLife, the findings suggest that interventions to prevent delirium in advance of surgery could help cardiac patients avoid long-term cognitive consequences.
A state of confusion that can develop following illness, infection or surgery, delirium is one of the most common complications in hospitalized patients over age 65. “Our findings now suggest that postoperative delirium, once thought of as an acute, transient cognitive disorder, may have longer-term effects on cognitive function in patients undergoing cardiac surgery,” said co-lead author Jane Saczynski, PhD, assistant professor of medicine at the University of Massachusetts Medical School.
While delirium has been studied quite extensively in other patient populations, including general medical and surgical patients and orthopedic surgery patients, few studies of delirium have targeted cardiac surgery patients. “With the aging of the patient population undergoing cardiac surgery and increases in survival after surgery, clinicians and patients are increasingly concerned with factors associated with quality of life, including cognitive status, as major outcomes of surgery,” the authors write. “Whether postoperative delirium is associated with prolonged cognitive dysfunction has been unclear.”
The researchers followed 225 patients, aged 60 to 90, who underwent either coronary artery bypass grafting (CABG) or heart valve replacement surgery at Beth Israel Deaconess Medical Center (BIDMC), UMass Memorial Medical Center or the Boston VA Medical Center, for one year after their surgeries, assessing them for both delirium and cognitive impairment.
“One of the real strengths of our study is that we assessed patients' cognitive function preoperatively and an average of five times during the year after surgery,” said co-lead author Edward Marcantonio, MD, section chief for research in BIDMC's Division of General Medicine and Primary Care and professor of medicine at Harvard Medical School. “Previous research had shown an association between postoperative delirium and functional decline in activities of daily living [such as grooming and dressing, driving, shopping, preparing meals and managing medications and finances.] But, believe it or not, the one thing that's been most uncertain is the association between delirium and long-term cognitive difficulties. This study allowed us to accurately model the course of cognitive function and to compare the rate of recovery among patients with and without postoperative delirium.”
The results showed that compared with patients who did not experience delirium, the 103 patients who developed delirium after cardiac surgery – 46 percent of the total – experienced a more significant drop in cognitive performance immediately following surgery, as determined by the Mini-Mental State Examination (MMSE). They also took significantly longer to recover back to their pre-surgical level of function than did patients who did not develop delirium. For example, five days after surgery, nearly half of those who did not develop delirium had returned to pre-operative levels of function while less than 20 percent of those who did develop delirium had returned to pre-operative level of function; six months after surgery, more than three-quarters of those without delirium had recovered cognitively compared to only 60 percent of those with delirium.
Although patients who developed delirium took longer to recover to their pre-operative levels of cognitive performance, they continued to improve in the weeks and months after surgery. Cognitive performance reached preoperative levels and stabilized one month after surgery in patients who did not develop delirium but continued to improve until six months after surgery in those with delirium.
These findings suggest that identifying patients at high risk for delirium prior to surgery and promoting the use of interventions to prevent delirium in cardiac surgical patients may have substantial benefits. It could improve the recovery rate of cognitive abilities and enhance functional recovery following surgery.
Further cognitive screening at discharge may also identify patients who require closer, post-operative monitoring or tailored transitional care to enhance the return of cognitive functions. “Since patients who experience delirium continue to show improvement in cognitive function six months after surgery, extending additional rehabilitation services to these patients may have added benefits,” said co-senior author Richard N. Jones, ScD, director of mental health and aging at Hebrew SeniorLife and assistant professor of medicine at Harvard Medical School.
“The findings from this study highlight the clinical importance of the identification of delirium and the potential of preventive interventions like the Hospital Elder Life Program [HELP],” said co-senior author Sharon K. Inouye, MD, MPH, director of the Aging Brain Center at Hebrew SeniorLife and professor of medicine at Harvard Medical School. “Although it is possible to identify patients at high risk for developing delirium and preventive interventions for delirium exist, these interventions have not been well tested in patients undergoing cardiac surgery. Additional development and testing of these interventions need to be studied in this patient population to accurately assess the potential benefits for cardiac patients.”
“More than half a million heart surgeries are performed each year,” said Marcantonio. “Our findings provide important information that might help doctors design interventions to improve the outcomes of older adults undergoing cardiac surgeries.” (Source: EurekAlert! A service of AAAS and University of Massachusetts Medical School).
Preventing or better managing diabetes may prevent cognitive decline, according to UCSF study
Preventing diabetes or delaying its onset has been thought to stave off cognitive decline -- a connection strongly supported by the results of a 9-year study led by researchers at the University of California, San Francisco (UCSF) and the San Francisco VA Medical Center.
Earlier studies have looked at cognitive decline in people who already had diabetes. The new study is the first to demonstrate that the greater risk of cognitive decline is also present among people who develop diabetes later in life. It is also the first study to link the risk of cognitive decline to the severity of diabetes.
The result is the latest finding to emerge from the Health, Aging, and Body Composition (Health ABC) Study, which enrolled 3,069 adults over 70 at two community clinics in Memphis, TN and Pittsburgh, PA beginning in 1997. All the patients provided periodic blood samples and took regular cognitive tests over time.
When the study began, hundreds of those patients already had diabetes. A decade later, many more of them had developed diabetes, and many also suffered cognitive decline. As described this week in Archives of Neurology, those two health outcomes were closely linked.
People who had diabetes at the beginning of the study showed a faster cognitive decline than people who developed it during the course of the study—and these people, in turn, tended to be worse off than people who never developed diabetes at all. The study also showed that patients with more severe diabetes who did not control their blood sugar levels as well suffered faster cognitive declines.
“Both the duration and the severity of diabetes are very important factors,” said Kristine Yaffe, MD, the lead author of the study. “It's another piece of the puzzle in terms of linking diabetes to accelerated cognitive aging.”
An important question for future studies, she added, would be to ask if interventions that would effectively prevent, delay or better control diabetes would also lower people's risk of cognitive impairment later in life.
Yaffe is the Roy and Marie Scola Endowed Chair of Psychiatry; professor in the UCSF departments of Psychiatry, Neurology and Epidemiology and Biostatistics; and Chief of Geriatric Psychiatry and Director of the Memory Disorders Clinic at the San Francisco VA Medical Center.
Diabetes and Cognitive Decline
Diabetes is a chronic and complex disease marked by high levels of sugar in the blood that arise due to problems with the hormone insulin, which regulates blood sugar levels. It is caused by an inability to produce insulin (type 1) or an inability to respond correctly to insulin (type 2).
A major health concern in the United States, diabetes of all types affects an estimated 8.3 percent of the U.S. population – some 25.8 million Americans – and costs U.S. taxpayers more than $200 billion annually. In California alone, an estimated 4 million people (one out of every seven adults) has type 2 diabetes and millions more are at risk of developing it. These numbers are poised to explode in the next half century if more is not done to prevent the disease.
Over the last several decades, scientists have come to appreciate that diabetes affects many tissues and organs of the body, including the brain and central nervous system—particularly because diabetes places people at risk of cognitive decline later in life.
In their study the scientists looked at a blood marker known as “glycosylated hemoglobin,” a standard measure of the severity of diabetes and the ability to control it over time. The marker shows evidence of high blood sugar because these sugar molecules become permanently attached to hemoglobin proteins in the blood. Yaffe and her colleagues found that greater levels of this biomarker were associated with more severe cognitive dysfunction.
While the underlying mechanism that accounts for the link between diabetes and risk of cognitive decline is not completely understood, Yaffe said, it may be related to a human protein known as insulin degrading enzyme, which plays an important role in regulating insulin, the key hormone linked to diabetes. This same enzyme also degrades a protein in the brain known as beta-amyloid, a brain protein linked to Alzheimer's disease. (Source: EurekAlert! A service of AAAS and University of California - San Francisco).
Revolutionary project will obtain entire genome sequences in fight against Alzheimer's
UCLA Laboratory of Neuro Imaging to partner in new effort to combat disease
Since 2004, UCLA's Laboratory of Neuro Imaging (LONI) has been responsible for receiving, organizing, archiving and disseminating the stream of data generated by the Alzheimer's Disease Neuroimaging Initiative (ADNI), an ambitious, worldwide effort by scientists to define the progression of Alzheimer's disease.
That stream of data will now turn into a flood, as LONI partners with an ambitious public–private effort to dig deeper into the causes of this devastating disease by obtaining the whole-genome sequencing of the more than 800 people enrolled in ADNI — the largest cohort of individuals related to a single disease.
This work is expected to generate at least 165 terabytes of new genetic data, an amount roughly equivalent to the information contained in 165,000 entire copies of the Encyclopedia Britannica.
“This effort, involving almost 60 sites around the country, is the best chance we have for understanding this brutal disease,” said LONI director Arthur Toga, a UCLA professor of neurology and one of the collaborators on the management of the sequencing efforts. “We collect vast amounts of imaging, cognitive and biosample data from hundreds of subjects with Alzheimer's disease, those at risk, and controls. One of the more unique aspects of this study is that all data are shared with any scientist, without embargo. We have already engaged many scientists around the world with this open access.”
The new genome project is a significant extension of ADNI, which now enrolls people with Alzheimer's disease, mild cognitive impairment and normal cognition who have agreed to be studied in great detail over time. The goal is to identify and understand markers of the disease with the hope of improving early diagnosis and accelerating the discovery of new treatments.
All of the ADNI data continues to flow into UCLA's LONI, including detailed, long-term assessments of neuropsychological measures, standardized structural and functional imaging, and precise biomarker measures from blood and spinal fluid. Now, added to this wealth of information will be the ADNI participants' entire genome sequences, which determine all 6 billion letters in an individual's DNA in one comprehensive analysis.
Once the sequences are completed — approximately 16 weeks after the sequencing project starts — the raw data will rapidly be made available to qualified scientists around the globe to mine for novel targets for risk-assessment, new therapies and much-needed insights into the causes of Alzheimer's.
All of the information from ADNI has always been made freely available, without delay, to scientists; to date, this has resulted in more than 500 scientific manuscripts.
ADNI is a public–private research project led by the National Institutes of Health with private sector support through the Foundation for NIH. Launched in 2004, ADNI's public–private funding consortium includes pharmaceutical companies, science-related businesses and nonprofit organizations, including the Alzheimer's Association and the Northern California Institute for Research and Education.
The ADNI whole-genome sequencing is being funded through a partnership between the Alzheimer's Association and the nonprofit Brin Wojcicki Foundation, a charitable organization created by Anne Wojcicki, founder of the online genetics firm 23andMe, and her husband, Sergey Brin, co-founder of Google.
“Sequencing the ADNI participants and making the genetic data immediately available to researchers around the world will significantly improve our understanding and approach to Alzheimer's disease,” Anne Wojcicki said.“The ADNI team and the Alzheimer's Association are impressive in their ability to quickly make decisions that are truly in the best interest of people with Alzheimer's.”
“Linking these deep-sequencing data with imaging and other data may help solve the puzzles in Alzheimer's that still vex us,” Toga said. “Certainly, a more complete picture will emerge, hopefully leading to effective therapies.” (Source: EurekAlert! A service of AAAS and University of California - Los Angeles).
Nutrient mixture improves memory in patients with early Alzheimer's
In clinical trial, mixture developed at MIT appears to help overcome loss of connections between brain cells
CAMBRIDGE, MA -- A clinical trial of an Alzheimer's disease treatment developed at MIT has found that the nutrient cocktail can improve memory in patients with early Alzheimer's. The results confirm and expand the findings of an earlier trial of the nutritional supplement, which is designed to promote new connections between brain cells.
Alzheimer's patients gradually lose those connections, known as synapses, leading to memory loss and other cognitive impairments. The supplement mixture, known as Souvenaid, appears to stimulate growth of new synapses, says Richard Wurtman, a professor emeritus of brain and cognitive sciences at MIT who invented the nutrient mixture.
“You want to improve the numbers of synapses, not by slowing their degradation — though of course you'd love to do that too — but rather by increasing the formation of the synapses,” Wurtman says.
To do that, Wurtman came up with a mixture of three naturally occurring dietary compounds: choline, uridine and the omega-3 fatty acid DHA. Choline can be found in meats, nuts and eggs, and omega-3 fatty acids are found in a variety of sources, including fish, eggs, flaxseed and meat from grass-fed animals. Uridine is produced by the liver and kidney, and is present in some foods as a component of RNA.
These nutrients are precursors to the lipid molecules that, along with specific proteins, make up brain-cell membranes, which form synapses. To be effective, all three precursors must be administered together.
Results of the clinical trial, conducted in Europe, appear in the July 10 online edition of the Journal of Alzheimer's Disease.
Plans for commercial release of the supplement are not finalized, according to Nutricia, the company testing and marketing Souvenaid, but it will likely be available in Europe first. Nutricia is the specialized health care division of the food company Danone, known as Dannon in the United States.
Making connections
Wurtman first came up with the idea of targeting synapse loss to combat Alzheimer's about 10 years ago. In animal studies, he showed that his dietary cocktail boosted the number of dendritic spines, or small outcroppings of neural membranes, found in brain cells. These spines are necessary to form new synapses between neurons.
Following the successful animal studies, Philip Scheltens, director of the Alzheimer Center at VU University Medical Center in Amsterdam, led a clinical trial in Europe involving 225 patients with mild Alzheimer's. The patients drank Souvenaid or a control beverage daily for three months.
That study, first reported in 2008, found that 40 percent of patients who consumed the drink improved in a test of verbal memory, while 24 percent of patients who received the control drink improved their performance.
The new study, performed in several European countries and overseen by Scheltens as principal investigator, followed 259 patients for six months. Patients, whether taking Souvenaid or a placebo, improved their verbal-memory performance for the first three months, but the placebo patients deteriorated during the following three months, while the Souvenaid patients continued to improve. For this trial, the researchers used more comprehensive memory tests taken from the neuropsychological test battery, often used to assess Alzheimer's patients in clinical research.
Patients showed a very high compliance rate: About 97 percent of the patients followed the regimen throughout the study, and no serious side effects were seen.
Both clinical trials were sponsored by Nutricia. MIT has patented the mixture of nutrients used in the study, and Nutricia holds the exclusive license on the patent.
Brain patterns
In the new study, the researchers used electroencephalography (EEG) to measure how patients' brain-activity patterns changed throughout the study. They found that as the trial went on, the brains of patients receiving the supplements started to shift from patterns typical of dementia to more normal patterns. Because EEG patterns reflect synaptic activity, this suggests that synaptic function increased following treatment, the researchers say.
Patients entering this study were in the early stages of Alzheimer's disease, averaging around 25 on a scale of dementia that ranges from 1 to 30, with 30 being normal. A previous trial found that the supplement cocktail does not work in patients with Alzheimer's at a more advanced stage. This makes sense, Wurtman says, because patients with more advanced dementia have probably already lost many neurons, so they can't form new synapses.
A two-year trial involving patients who don't have Alzheimer's, but who are starting to show mild cognitive impairment, is now underway. If the drink seems to help, it could be used in people who test positive for very early signs of Alzheimer's, before symptoms appear, Wurtman says. Such tests, which include PET scanning of the hippocampus, are now rarely done because there are no good Alzheimer's treatments available. (Source: EurekAlert! A service of AAAS and Massachusetts Institute of Technology).
First detailed timeline established for brain's descent into Alzheimer's
Scientists have assembled the most detailed chronology to date of the human brain's long, slow slide into full-blown Alzheimer's disease.
The timeline, developed through research led by scientists at Washington University School of Medicine in St. Louis, appears July 11 in The New England Journal of Medicine.
As part of an international research partnership known as the Dominantly Inherited Alzheimer's Network (DIAN), scientists at Washington University and elsewhere evaluated a variety of pre-symptomatic markers of Alzheimer's disease in 128 subjects from families genetically predisposed to develop the disorder. Individuals in the study have a 50 percent chance of inheriting one of three mutations that are certain to cause Alzheimer's, often at an unusually young age.
Using medical histories of the subjects' parents to estimate the age of the onset of symptoms for the study participants, the scientists assembled a timeline of changes in the brain leading to the memory loss and cognitive decline that characterizes Alzheimer's. The earliest of these changes, a drop in spinal fluid levels of the key ingredient of Alzheimer's brain plaques, can be detected 25 years before the anticipated age of onset.
“A series of changes begins in the brain decades before the symptoms of Alzheimer's disease are noticed by patients or families, and this cascade of events may provide a timeline for symptomatic onset,” says first author Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine in St. Louis. “As we learn more about the origins of Alzheimer's to plan preventive treatments, this Alzheimer's timeline will be invaluable for successful drug trials.”
As an example, Bateman says that the new data show that plaques become visible on brain scans 15 years before memory problems become apparent. Researchers in the DIAN plan to give treatments that remove or block plaque formation at this early stage of the disease's progression and monitor subjects to see not only if the plaques can be prevented or reduced, but also whether other Alzheimer's biomarkers measured in the study improve.
Primarily funded by the National Institutes of Health (NIH), the DIAN partnership is researching the rare, familial form of Alzheimer's disease that can cause symptoms to appear in affected people in their 30s and 40s--decades earlier than the more common form that typically occurs after age 65.
“These exciting findings are the first to confirm what we have long suspected, that disease onset begins years before the first sign of cognitive decline or memory loss,” said Laurie Ryan, PhD, clinical trials program director at the National Institute on Aging, part of the NIH. “And while DIAN participants are at risk for the rare, genetic form of the disease, insights gained from the study will greatly inform our understanding of late-onset Alzheimer's disease.”
Because individuals with these inherited forms of Alzheimer's are widely dispersed geographically, there are too few at any one center to conduct extensive research. That led DIAN principal investigator John C. Morris, MD, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology at Washington University, and his team to form the network four years ago.
“These new results could never have been gathered without the collaborative teamwork and dedication of our DIAN partners at institutions across the United States and in the United Kingdom and Australia,” says Morris, who also is director of the Charles F. and Joanne Knight Alzheimer's Disease Research Center at Washington University.
Other results from the new study include:
Elevated spinal fluid levels of tau, a structural protein in brain cells, appear 15 years before Alzheimer's symptoms.
Shrinkage in key brain structures becomes discernible 15 years before symptoms.
Decreases in the brain's use of the sugar glucose and slight impairments in a specific type of memory are detectable 10 years before symptoms.
Researchers also tested participants from DIAN families who do not have any of the mutations that cause inherited Alzheimer's.
“Family members without the Alzheimer's mutations have no detected change in the markers we tested,” Bateman says.“It's striking how normal the Alzheimer's markers are in family members without a mutation.”
Bateman is leading the development of Alzheimer's prevention and treatment trials in DIAN participants. He and his colleagues hope to launch trials later this year.
DIAN researchers now offer an expanded registry for families with inherited Alzheimer's mutations. They encourage anyone with a family history of multiple generations of Alzheimer's diagnosed before age 55 to visit http://www.DIANXR.org/, where they can register for follow-up contact from researchers to determine whether their family is eligible for participation in DIAN studies. (Source: EurekAlert! A service of AAAS and Washington University School of Medicine).
New biomarker in the blood may help predict Alzheimer's disease
MINNEAPOLIS – Higher levels of a certain fat in the blood called ceramides may increase a person's risk of developing Alzheimer's disease, according to a study published in the July 18, 2012, online issue of Neurology ®, the medical journal of the American Academy of Neurology.
“Our study identifies this biomarker as a potential new target for treating or preventing Alzheimer's disease,” said study author Michelle M. Mielke, PhD, an epidemiologist with the Mayo Clinic in Rochester, Minn. Mielke was with Johns Hopkins University at the time of the research.
For the study, 99 women between the ages of 70 and 79 and free of dementia in the Women's Health and Aging Study II had their blood tested for levels of serum ceramides, a fatty compound found throughout the body that is associated with inflammation and cell death. The participants were placed into three groups: high, middle and low levels of ceramides. They were then followed for up to nine years. Of the 99 participants, 27 developed dementia and 18 of those were diagnosed with probable Alzheimer's disease.
The study found that women who had the highest levels of the biomarker were 10 times more likely to develop Alzheimer's disease than women with the lowest levels. Those with middle levels of the biomarker were nearly eight times more likely to develop the disease than those with the lowest levels.
“These findings are important because identifying an accurate biomarker for early Alzheimer's that requires little cost and inconvenience to a patient could help change our focus from treating the disease to preventing or delaying it,” said Valory Pavlik, PhD, with the Alzheimer's Disease and Memory Disorders Center of Baylor College of Medicine in Houston and a member of the American Academy of Neurology, in an accompanying editorial.
According to Pavlik, “While a larger, more diverse study is needed to confirm these findings, projections that the global prevalence of Alzheimer's disease will double every 20 years for the foreseeable future have certainly increased the sense of urgency among researchers and health care agencies to identify more effective screening, prevention and treatment strategies.” (Source: EurekAlert! A service of AAAS and American Academy of Neurology).
New drug could treat Alzheimer's, multiple sclerosis and brain injury
1-size-fits-all drug targets harmful brain inflammation in many diseases
CHICAGO --- A new class of drug developed at Northwestern University Feinberg School of Medicine shows early promise of being a one-size-fits-all therapy for Alzheimer's disease, Parkinson's disease, multiple sclerosis and traumatic brain injury by reducing inflammation in the brain.
Northwestern has recently been issued patents to cover this new drug class and has licensed the commercial development to a biotech company that has recently completed the first human Phase 1 clinical trial for the drug.
The drugs in this class target a particular type of brain inflammation, which is a common denominator in these neurological diseases and in traumatic brain injury and stroke. This brain inflammation, also called neuroinflammation, is increasingly believed to play a major role in the progressive damage characteristic of these chronic diseases and brain injuries.
By addressing brain inflammation, the new class of drugs -- represented by MW151 and MW189 -- offers an entirely different therapeutic approach to Alzheimer's than current ones being tested to prevent the development of beta amyloid plaques in the brain. The plaques are an indicator of the disease but not a proven cause.
A new preclinical study published today in the Journal of Neuroscience, reports that when one of the new Northwestern drugs is given to a mouse genetically engineered to develop Alzheimer's, it prevents the development of the full-blown disease. The study, from Northwestern's Feinberg School and the University of Kentucky, identifies the optimal therapeutic time window for administering the drug, which is taken orally and easily crosses the blood-brain barrier.
“This could become part of a collection of drugs you could use to prevent the development of Alzheimer's,” said D. Martin Watterson, a professor of molecular pharmacology and biological chemistry at the Feinberg School, whose lab developed the drug. He is a coauthor of the study.
In previous animal studies, the same drug reduced the neurological damage caused by closed-head traumatic brain injury and inhibited the development of a multiple sclerosis-like disease. In these diseases as well as in Alzheimer's, the studies show the therapy time window is critical.
MW151 and MW189 work by preventing the damaging overproduction of brain proteins called proinflammatory cytokines. Scientists now believe overproduction of these proteins contributes to the development of many degenerative neurological diseases as well as to the neurological damage caused by traumatic brain injury and stroke.
When too many of the cytokines are produced, the synapses of the brain begin to misfire. Eventually the entire organization of the brain falls into disarray, like a computer failing. The neurons lose their connections with each other and can eventually die. The resulting damage in the cortex and hippocampus can compromise memory and decision-making.
“In Alzheimer's disease, many people now view the progression from mild cognitive impairment to full-blown Alzheimer's as an indication of malfunctioning synapses, the pathways that allow neurons to talk to each other,” said Watterson, the John G. Searle Professor of Molecular Biology and Biochemistry. “And high levels of proinflammatory cytokines can contribute to synaptic malfunction.”
Because this harmful inflammatory mechanism also appears to be a major player in other neurodegenerative disorders in addition to Alzheimer's, the class of drugs represented by MW151 might hold bright potential as co-therapies for Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, M.S. and the longer term complications of brain injury, Watterson said.
“We need more studies of therapeutic time windows in models of these other diseases so we can better plan future clinical trials,” Watterson noted.
In the new study by Northwestern's Watterson and Linda Van Eldik, director of the University of Kentucky Sanders-Brown Center on Aging, a mouse model of Alzheimer's received MW151 three times a week starting at six months of age, right at the time the proinflammatory cytokines began to rise. This would be the comparable stage when a human patient would begin to experience mild cognitive impairment.
When the mice brains were later evaluated at 11 months (at a time when disease pathology is usually present), cytokine levels in the mice receiving the drug were restored to normal levels and their synapses were functioning normally. The inflammatory cytokine levels of the mice not receiving the drug, however, were still at abnormally high levels, and the mice had misfiring synapses.
“The drug protected against the damage associated with learning and memory impairment,” Van Eldik noted. “Giving this drug before Alzheimer's memory changes are at a late stage may be a promising future approach to therapy.”
Drug inhibits multiple sclerosis development
In M.S., overproduction of the proinflammatory cytokines damage the central nervous system and the brain. The proteins directly or indirectly destroy the insulation or coverings of the nerve cells that transmit signals down the spinal cord. When the insulation is stripped, messages aren't properly conducted down the spinal cord.
When mice that were induced to develop an M.S.-like disease received MW151 orally, they did not develop disease as severe.
“We inhibited the development of the disease,” said William Karpus, the Marie A. Fleming Research Professor of Pathology at the Feinberg School. “Now we need to learn if the drug can prevent relapses of M.S.” That study is ongoing in mice and the results will determine whether a patient trial will be planned.
The only current oral drug treatment for M.S. acts at the level of the lymph nodes, Karpus said. Because the brain is the site of the inflammation and damage, a drug that works in the brain is an ideal therapy.
Drug protects brain after traumatic brain injury
After a traumatic brain injury, the glia cells in the brain become hyperactive and release a continuous cascade of proinflammatory cytokines that -- in the long term -- can result in cognitive impairment and epilepsy. As a result of this hyperactivity, researchers believe the brain is more susceptible to serious damage following a second neurological injury.
In a study with mice, Mark Wainright, M.D., professor of pediatric neurology at Northwestern's Feinberg School and a physician at the Ann & Robert H. Lurie Children's Hospital of Chicago, showed that when MW151 is given during an early therapeutic window three to six hours after the injury, it blocks glial activation and prevents the flood of proinflammatory cytokines after a traumatic brain injury.
“If you took a drug like this early on after traumatic brain injury or a even a stroke, you could possibly prevent the long-term complications of that injury including the risk of seizures, cognitive impairment and, perhaps, mental health issues,” Wainwright said.
Stroke also causes inflammation in the brain that may also be linked to long-term complications including epilepsy and cognitive deficits. As in traumatic brain injury, this inflammatory response is part of the recovery mechanisms used by the brain, so the use of brief and focused treatments like MW151 could prevent the harmful effects of inflammation while allowing the protective effects to occur unimpeded.
In another study, Wainwright showed MW151, when given after a traumatic brain injury, prevented the increased risk of epileptic seizures. (Source: EurekAlert! A service of AAAS and Northwestern University).
Alzheimer's cognitive decline slows in advanced age
The greatest risk factor for Alzheimer's disease (AD) is advancing age. By age 85, the likelihood of developing the dreaded neurological disorder is roughly 50 percent. But researchers at the University of California, San Diego School of Medicine say AD hits hardest among the “younger elderly” – people in their 60s and 70s – who show faster rates of brain tissue loss and cognitive decline than AD patients 80 years and older.
The findings, reported online in the August 2, 2012 issue of the journal PLOS One, have profound implications for both diagnosing AD – which currently afflicts an estimated 5.6 million Americans, a number projected to triple by 2050 – and efforts to find new treatments. There is no cure for AD and existing therapies do not slow or stop disease progression.
“One of the key features for the clinical determination of AD is its relentless progressive course,” said Dominic Holland, PhD, a researcher at the Department of Neurosciences at UC San Diego and the study's first author. “Patients typically show marked deterioration year after year. If older patients are not showing the same deterioration from one year to the next, doctors may be hesitant to diagnose AD, and thus these patients may not receive appropriate care, which can be very important for their quality of life.”
Holland and colleagues used imaging and biomarker data from participants in the Alzheimer's Disease Neuroimaging Initiative, a multi-institution effort coordinated at UC San Diego. They examined 723 people, ages 65 to 90 years, who were categorized as either cognitively normal, with mild cognitive impairment (an intermediate stage between normal, age-related cognitive decline and dementia) or suffering from full-blown AD.
“We found that younger elderly show higher rates of cognitive decline and faster rates of tissue loss in brain regions that are vulnerable during the early stages of AD,” said Holland. “Additionally cerebrospinal fluid biomarker levels indicate a greater disease burden in younger than in older individuals.”
Holland said it's not clear why AD is more aggressive among younger elderly.
“It may be that patients who show onset of dementia at an older age, and are declining slowly, have been declining at that rate for a long time,” said co-author Linda McEvoy, PhD, associate professor of radiology. “But because of cognitive reserve or other still-unknown factors that provide ‘resistance’ against brain damage, clinical symptoms do not manifest till later age.”
Another possibility, according to Holland, is that older patients may be suffering from mixed dementia – a combination of AD pathology and other neurological conditions. These patients might withstand the effects of AD until other adverse factors, such as brain lesions caused by cerebrovascular disease, take hold. At the moment, AD can only be diagnosed definitively by an autopsy. “So we do not yet know the underlying neuropathology of participants in this study,” Holland said.
Clinical trials to find new treatments for AD may be impacted by the differing rates, researchers said. “Our results show that if clinical trials of candidate therapies predominately enroll older elderly, who show slower rates of change over time, the ability of a therapy to successfully slow disease progression may not be recognized, leading to failure of the clinical trial,” said Holland. “Thus, it's critical to take into account age as a factor when enrolling subjects for AD clinical trials.”
The obvious downside of the findings is that younger patients with AD lose more of their productive years to the disease, Holland noted. “The good news in all of this is that our results indicate those who survive into the later years before showing symptoms of AD will experience a less aggressive form of the disease.” (Source: EurekAlert! A service of AAAS and University of California - San Diego).