Abstract
Analyst Insight: Alzheimer’s Efforts Shift from Cure to Prevention: Emerging Biomarkers, and Possible Ties to Diabetes
LONDON, UK, 14 September 2012 - World Alzheimer’s Action Day, September 21st, is an opportunity to raise awareness about Alzheimer’s disease, including the need for further education, clinical research and support. Over 5.4 million Americans (and 36 million people worldwide) currently suffer from Alzheimer’s Disease (AD), supported by over $200 billion in direct US healthcare costs. Moreover, AD poses real challenges for both the person diagnosed as well as those who assume caregiving responsibilities - over 15 million Americans provide unpaid care and support for family members suffering from the disease, for a combined national bill of over $210 billion in unpaid care. AD causes abnormal changes in the brain, mainly affecting memory and other mental abilities, and can lead to loss of reasoning ability, language, decision-making capacity, judgment and other critical skills. The condition's prevalence is expected to quadruple by 2050.
While the cause and progression of AD are not fully understood, increasing evidence indicates that the first chemical changes in the brain happen as many as 20 years before symptoms of dementia are exhibited. Recent studies have dramatically changed both the diagnosis and treatment of AD, and we believe the future promises significant advances in research and care related to prevention and early diagnosis of this degenerative disease.
The year 2012 has been momentous for AD in terms of progressing research, guidelines for therapy, government funding, and services. In May, at the Alzheimer’s Research Summit, the Department of Health and Human Services (HHS) released an ambitious national plan to fight AD. The plan was called for in the National Alzheimer’s Project Act (NAPA), signed in by President Obama in January 2011. The HHS plan sets forth goals for prevention and treatment, in conjunction with a proposed FY 2013 budget that provides a $100m increase in funding for combative AD research. Following new recommendations for diagnostic criteria and guidelines released in 2011 by the National Institute on Aging (NIA), this plan calls for a comprehensive, collaborative approach across federal, state, private, and non-profit organizations; more than 3,600 people or organizations submitted comments on the plan’s draft.
The NIA last released AD diagnostic guidelines back in 1984, based largely on various physicians’ judgments of disease causes, in addition to observable symptoms. This outdated criteria for AD qualified patients primarily by cognitive function and ability, disregarding asymptomatic individuals who may already be suffering from neuronal degradation. The 2011 guidelines consider the entire continuum of the disease, including screening for preclinical patients to detect AD in its earliest stages, before memory is affected.
In an effort to discover and validate the next generation of therapeutic targets for AD, researchers are constantly looking to improve their methods. With an aim to better diagnostics, work has been proposed to develop robust biomarkers, including metabolic signatures to develop and validate diagnostic, prognostic, and surrogate biomarkers for AD and its subtypes. Additionally, there is interest to facilitate the conversion of existing genetic information into mechanistic insights and therapeutic advances. As AD treatment undergoes a paradigm shift from cure to prevention, numerous clinical trials are ramping up to further examine the relationship between specific biomarkers and disease prevalence. Currently, clinical diagnosis of AD is inaccurate even among experienced investigators in about 15% of cases, and biomarkers may hold the key to improved diagnostic accuracy. In a notable UC Santa Barbara clinical trial starting in 2013, researchers in the US and Columbia are tracing AD to a specific genetic mutation. Biomarkers can be identified using magnetic resonance imaging and Positron Emission Tomography (PET) to assess glucose utilization, extracellular beta-amyloid plaque accumulation, or intracellular phosphorylated tau protein deposits. Combining diagnostics with medical device imaging, Eli Lilly & Co. received FDA approval in the spring of 2012 for a PET scan and accompanying radioactive tag that can detect and measure amyloid concentrations in the brain. Numerous academic institutions are investigating the use of medical device imaging for AD diagnostics, although this practice is not standard yet. As biomarkers advance diagnostics, GlobalData understands it would be strategically beneficial for pharmaceutical companies in therapy development and biotech companies working on biomarker discovery to form collaborative alliances or partnerships. In an example of such an alliance already in place, Pfizer and Exonhit (a French biotech company) are working together to develop biomarkers for AD using Exonhit’s SpliceArray platform. Exonhit is also currently developing AclarusDx, a blood-based biomarker test for AD that is in the clinical stage in the US and France.
In regards to a cure, treatments targeting accumulation of beta-amyloid are some of the furthest along in development; these protein plaques have long been considered an AD hallmark. Currently, two strategies aimed at beta-amyloid are being investigated, including immunizing the body against it and blocking its production. In two 2012 Phase III failures, Pfizer and Johnson & Johnson (bapineuzumab) as well as Eli Lilly & Co. (solanezumab) were disappointed their anti-amyloid drugs failed to improve AD patients’ memory or thinking. However, deeper analysis of the various study results indicate that anti-amyloid drugs are efficacious in their targeted approach and actually reduce levels of amyloid in the brain. It has been suggested that this approach would be more effective in impacting disease progression if implemented earlier, and to this end, three complementary prevention trials starting in the fall of 2012 will test whether anti-amyloid treatments are effective in asymptomatic AD patients; however, these trials could take years to complete.
In the wake of the recent failures of pharmaceutical giants, competitor Roche Holdings now has the upper hand, as its four pipeline products continue to show promise. Of these four drugs, two have shown considerable potential. The NIH has recently agreed to sponsor a trial looking at Roche’s crenezumab drug, and its gantenerumab drug has been shown to reduce amyloid levels more rapidly than competitors. It’s worth mentioning that in the past week Roche has doubled the number of patients in their gantenerumab trial. This may be in reaction to an anticipated Pfizer data presentation on efficacy in amyloid clearing. Moreover, Roche’s clinical approach with approving gantenerumab is different from Eli Lilly and Pfizer as Roche is targeting patients in the earlier stages of AD, which may yield more promising results. While there is unknown risk related to the success or failure of these drugs, a Roche drug approval for AD indications would boost the company’s sales to a large extent.
AstraZeneca played catch-up in 2012, acquiring US biotech Link Medicine in July with hopes to come up with several AD drugs in late-stage clinical trials over the next three years. Meanwhile, GlaxoSmithKline, who signed a collaboration agreement in 2008 with Affiris GmbH, has several ongoing Phase II trials, though few reported results thus far. Merck, on the other hand, has multiple preclinical and clinical studies ongoing to investigate the safety and efficacy of their anti-amyloid drug family, including MK-8931, their lead compound that completed Phase I trials in 2012. Currently, there are only five FDA-approved medications for AD, all of which only treat symptoms.
In another recent study, researchers have shown that insulin improves memory in AD patients, and nasal spray devices have enabled rapid insulin delivery to the brain. In a Phase II study at the University of Washington investigating intranasal insulin therapy, results released in early 2012 were positive, showing net improvement of patient cognitive abilities and lower AD risk compared with participants taking placebo. Based on the promising outcome of this study, the National Institutes of Health has granted necessary funding to conduct a larger Phase III trial on 240 volunteers in 2013.
In light of these studies looking at the brain’s impaired response to insulin as it relates to AD, other researchers have hypothesized that Alzheimer’s may be related to diabetes; some going so far as to propose the name “type 3 diabetes”. The correlation between Alzheimer’s and type 2 diabetes is long established: diabetes patients are two to three times more likely to develop AD. Additionally, there are also associations between AD and obesity as well as AD and metabolic syndrome. The relationship between AD and insulin was first proposed in 2005 when a group of researchers noticed reduced insulin and insulin-like growth factor levels in the brains of AD patients. Experiments conducted since then have supported the link between diet and dementia; further research is needed to quantify this correlation, however.
In addition to drug development, researchers are working to collaborate on a worldwide scale. Through establishing AD registries, founding the new website www.alzheimers.gov, and furthering awareness campaigns, supporters have paved the road in 2012 for increased communication, cooperation, and deeper analysis of the underlying causes of AD.
In 2013, we expect new developments within amyloid vaccination and inhibition of hyperphosphorylation of tau, specifically in asymptomatic patients and early cases of AD. While Pfizer, J&J, and Eli Lilly have suffered major setbacks in 2012, Roche has recorded notable advancements and is a key player to watch. Investigations related to identifying biomarkers, as well as measuring them in patients, will continue to grow – especially with the FDA’s recent approval of Eli Lilly’s biomarker brain scan procedure. In 2013 we expect further research in regards to the correlation between diabetes and AD, which could have enormous implications as rates of obesity climb ever higher. (Source: GlobalData).
New diagnostic biomarkers offer ray of hope for Alzheimer's disease
Amsterdam, NL, August 29, 2012 – Alzheimer's disease (AD) is one of the most common brain disorders, with an estimated 35 million people affected worldwide. In the last decade, research has advanced our understanding of how AD affects the brain. However, diagnosis continues to rely primarily on neuropsychological tests which can only detect the disease after clinical symptoms begin. In a supplement to the Journal of Alzheimer's Disease, investigators report on the development of imaging-based biomarkers that will have an impact on diagnosis before the disease process is set in motion.
"There is an urgent need for the development of reliable diagnostic biomarkers that can detect AD pathology at an incipient phase," says Guest Editor Dr. Pravat Mandal, Adjunct Associate Professor of the Department of Radiology, Johns Hopkins Medicine, Baltimore, MD and Additional Professor, National Brain Research Center, India. "This special issue focuses on the latest strides made in identifying diagnostic biomarkers using state-of-the-art imaging modalities."
The issue looks at the application of various magnetic resonance imaging (MRI) technologies for diagnosing AD and monitoring the progression of the disease. For example, Brian T. Gold and colleagues report on the use of diffusion tension imaging (DTI) to identify changes in the white matter of patients with amnestic mild cognitive impairment (MCI), an early symptom of AD. Charles D. Smith and colleagues describe MRI-based detection of key structural alterations in cognitively normal subjects that can serve as a predictor of memory impairment.
While MRI provides information about the anatomy of the brain, functional MRI (fMRI) provides crucial information about the regions involved during specific tasks. The issue explores how fMRI can detect changes in functional activation and connectivity in AD patients. Monitoring alterations in functional brain activity related to visual processing deficits in AD has immense potential as an early diagnostic biomarker, according to a review by Dr. Mandal and colleagues. By using fMRI to study normal older individuals, patients with MCI, and those with AD as they perform cognitive tasks and at rest, Jasmeer P. Chhatwal and Reisa Sperling reveal the functional alterations associated with healthy aging as well as MCI and AD.
Magnetic resonance spectroscopy (MRS) is a powerful non-invasive imaging technique that can provide crucial information about neurochemical changes in AD. Dr. Mandal and colleagues report that the identification of neurochemical changes in the brains of MCI and AD patients may provide a "signature" of early AD pathology, and may aid in diagnosing patients who are moving from MCI to more advanced AD.
Imaging is also used to examine the molecular and therapeutic effects of potential AD treatments. Liam Zaidel and colleagues found that patients treated with donepezil for mild cognitive symptoms had a significant increase in interhemispheric functional connectivity of the left and right dorsolateral prefrontal cortices. Giulia Liberati and colleagues describe a non-invasive brain-computer interface that can detect a patient's emotional and cognitive state. It could provide vital information on the effect of clinical drugs on brain function and cognition in patients with AD.
The issue also includes a thought-provoking argument from Edo Richard and colleagues calling for a paradigm shift in dementia research and biomarker development. Current biomarker research focuses on correlates of plaques and tangles, which are poor markers in older dementia subjects. The authors suggest that the acknowledgement that dementia in older subjects is different from dementia at a young age will lead to new approaches in biomarker development and research.
"Research is needed to understand which molecular, structural, and functional changes are causally related to the onset of AD," says Dr. Mandal. "This special issue aims to conceptualize more effective and reliable biomarkers for AD."
George Perry, PhD, Editor-in-Chief, Journal of Alzheimer's Disease, and Dean and Professor, College of Sciences, University of Texas at San Antonio, says, "The development of biomarkers to aid in early detection of the onset of AD is critical. This special issue will spur research into multi-model imaging based biomarker development for AD." (Source: EurekAlert! A service of AAAS and IOS Press).
Cleveland Clinic researchers investigating potential drug for treatment of Alzheimer's disease
Compound interacts with receptor in brain that plays role in neurodegenerative processes in Alzheimer's disease
Friday, Aug. 31, 2012, Cleveland: A compound developed to treat neuropathic pain has shown potential as an innovative treatment for Alzheimer's disease, according to a study by researchers at Cleveland Clinic's Lerner Research Institute and Anesthesiology Institute.
"Cleveland Clinic dedicated two years of research into the examination of this compound and our findings show it could represent a novel therapeutic target in the treatment of Alzheimer's disease," said Mohamed Naguib, M.D., Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine. "Development of this compound as a potential drug for Alzheimer's would take many more years, but this is a promising finding worthy of further investigation."
In a study published online in the Neurobiology of Aging, the compound MDA7 induced beneficial immune responses that limited the development of Alzheimer's disease. Treatment with the compound restored cognition, memory and synaptic plasticity – a key neurological foundation of learning and memory – in an animal model.
Neuroinflammation is an important mechanism involved in the progression of Alzheimer's disease. The MDA7 compound has anti-inflammatory properties that act on the CB2 receptor – one of the two cannabinoid receptors in the body – but without the negative side effects normally seen with cannabinoid compounds.
Alzheimer's disease is an irreversible, fatal brain disease that slowly destroys memory and thinking skills. About 5 million people in the United States have Alzheimer's disease. With the aging of the population, and without successful treatment, there will be 16 million Americans and 106 million people worldwide with Alzheimer's by 2050, according to the 2011 Alzheimer's Disease Facts and Figures report from the Alzheimer's Association. (Source: EurekAlert! A service of AAAS and Cleveland Clinic).
Study in mice suggests sleep problems may be early sign of Alzheimer's
Sleep disruptions may be among the earliest indicators of Alzheimer's disease, scientists at Washington University School of Medicine in St. Louis report Sept. 5 in Science Translational Medicine.
Working in a mouse model, the researchers found that when the first signs of Alzheimer's plaques appear in the brain, the normal sleep-wake cycle is significantly disrupted.
"If sleep abnormalities begin this early in the course of human Alzheimer's disease, those changes could provide us with an easily detectable sign of pathology," says senior author David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of Washington University's Department of Neurology. "As we start to treat Alzheimer's patients before the onset of dementia, the presence or absence of sleep problems may be a rapid indicator of whether the new treatments are succeeding."
Holtzman's laboratory was among the first to link sleep problems and Alzheimer's through studies of sleep in mice genetically altered to develop Alzheimer's plaques as they age. In a study published in 2009, he showed that brain levels of a primary ingredient of the plaques naturally rise when healthy young mice are awake and drop after they go to sleep. Depriving the mice of sleep disrupted this cycle and accelerated the development of brain plaques.
A similar rising and falling of the plaque component, a protein called amyloid beta, was later detected in the cerebrospinal fluid of healthy humans studied by co-author Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University.
The new research, led by Jee Hoon Roh, MD, PhD, a neurologist and postdoctoral fellow in Holtzman's laboratory, shows that when the first indicators of brain plaques appear, the natural fluctuations in amyloid beta levels stop in both mice and humans.
"We suspect that the plaques are pulling in amyloid beta, removing it from the processes that would normally clear it from the brain," Holtzman says.
Mice are nocturnal animals and normally sleep for 40 minutes during every hour of daylight, but when Alzheimer's plaques began forming in their brains, their average sleep times dropped to 30 minutes per hour.
To confirm that amyloid beta was directly linked to the changes in sleep, researchers gave a vaccine against amyloid beta to a new group of mice with the same genetic modifications. As these mice grew older, they did not develop brain plaques. Their sleeping patterns remained normal and amyloid beta levels in the brain continued to rise and fall regularly.
Scientists now are evaluating whether sleep problems occur in patients who have markers of Alzheimer's disease, such as plaques in the brain, but have not yet developed memory or other cognitive problems.
"If these sleep problems exist, we don't yet know exactly what form they take—reduced sleep overall or trouble staying asleep or something else entirely," Holtzman says. "But we're working to find out." (Source: EurekAlert! A service of AAAS and Washington University School of Medicine).
Scientists dramatically reduce plaque-forming substances in mice with Alzheimer's disease
COLUMBUS, Ohio – Scientists have found that eliminating an enzyme from mice with symptoms of Alzheimer's disease leads to a 90 percent reduction in the compounds responsible for formation of the plaques linked to Alzheimer's disease.
That is the most dramatic reduction in this compound reported to date in published research.
The compounds are amyloid beta, or A-beta peptides; peptides are proteins, but are shorter in length. When A-beta peptides accumulate in excessive amounts in the brain, they can form plaques, which are a hallmark of Alzheimer's disease.
"These mice are models for the most aggressive form of Alzheimer's disease and produce the highest amount of A-beta peptides. This 90 percent reduction is the biggest drop in A-beta levels that has been reported so far by treating animal models with drugs or genetic manipulations," said Sung Ok Yoon, associate professor of molecular & cellular biochemistry at Ohio State University and lead author of the study.
The key to reducing A-beta peptides was the elimination of an enzyme called jnk3. This enzyme stimulates a protein that produces A-beta peptides, suggesting that when jnk3 activities are high, A-beta peptide production increases – increasing chances for their accumulation and formation into plaques.
The researchers also observed that jnk3 activities in brain tissue from Alzheimer's disease patients were increased by 30 to 40 percent when compared to normal human brain tissue. Jnk3 activity typically remains low in the brain, but increases when physiological abnormalities arise.
The findings suggest that jnk3 could be a new target for Alzheimer's disease intervention, Yoon said. So far, some drugs can slow the disease's progression, but there is no cure.
The research is published in the Sept. 6, 2012 issue of the journal Neuron.
Alzheimer's disease affects more than 5 million Americans, and its cause remains unknown. Although scientists have not yet determined whether A-beta peptides present in plaques cause Alzheimer's disease or form as a consequence of the disease, the presence of the plaques is linked to progressive cognitive decline.
In this study, Yoon and colleagues deleted jnk3 genetically from Alzheimer's disease model mice carrying the mutations that are found among early-onset Alzheimer's disease patients. In six months, the deletion of the enzyme had lowered A-beta peptide production by 90 percent, which persisted over time, with a 70 percent reduction seen at 12 months in these mice.
When the researchers saw that elimination of jnk3 dramatically lowered A-beta peptides in the mice, they also looked for effects on cognitive function at 12 months. The deletion of jnk3 improved cognitive function significantly, reaching 80 percent of normal, while cognitive function in disease model mice was 40 percent of normal. The number of brain cells, or neurons, in the Alzheimer's disease mice was also increased with jnk3 deletion, reaching 86 percent of the value in normal mice, while the neuron numbers were only 74 percent in Alzheimer's model mice.
Jnk3 is an enzyme that modifies its target proteins, changing the protein properties. Amyloid precursor protein (APP), which produces A-beta peptides, was already known to be modified in Alzheimer's disease brains. Yoon and colleagues also found that jnk3 modifies APP, which leads to stimulation of A-beta peptide production.
The scientists examined whether patterns of RNA expression in the Alzheimer's disease mouse brains were changed when jnk3 was deleted. This pattern tells scientists whether cells are behaving as expected. The results were a big surprise: Expression of genes that are necessary for new protein production, or synthesis, was significantly reduced in the Alzheimer's model brains compared to normal mouse brains.
"A lot of neurons had shut off their protein production. And when we deleted jnk3, the neurons' overall protein production came very close to normal levels," Yoon said.
Experiments in neuron cultures circled this phenomenon back to high levels of A-beta peptides, showing that A-beta peptides turn off new protein production by activating another enzyme called AMP kinase (AMPK). AMPK is normally activated when cells are starved of nutrients, such as right before a meal. For that reason, AMPK is a popular target in diseases associated with the body's use of glucose and fats for metabolism, such as Type 2 diabetes.
The researchers observed that once activated, AMPK eventually silenced a powerful sequence of chemical reactions called the mTOR pathway, which controls new protein synthesis in a variety of cell types. This phenomenon launches a stress response in the ER (endoplasmic reticulum), which is the protein synthesis machine present in every single cell.
"The interesting thing is, it had already been published that when ER stress is induced, that could activate jnk3," Yoon said.
As a result, she and her colleagues proposed a model to describe their hypothesis. Continual jnk3 activation by ER stress allows a detrimental cycle to start, and this cycle gets stronger over time as follows: An as-yet unidentified physiological problem increases jnk3 activity, which leads to initial production of A-beta peptides from APP. These peptides stimulate the AMPK enzyme. AMPK then blocks new protein production by the mTOR pathway. The lowered protein production leads to ER stress, and this increases jnk3 activities. As at the start, the increased jnk3 activities lead to production of more A-beta, adding "more push" to the cycle, Yoon explained.
"So, around and around and around it goes, ever more strongly. These results suggest that jnk3 is the key perpetuating the cycle," she said.
To test the hypothesis, the researchers treated live mouse brain tissues with one drug that blocks the mTOR pathway or another drug that induces ER stress. Both treatments dramatically increased A-beta peptide production within nine hours, but only when jnk3 was present. And revisiting the human data, the researchers also observed that Alzheimer's disease brain tissue showed a prominent elevation of ER stress.
Though a missing link remains – the pathological condition that produces this stress in the first place – Yoon said the demonstration that A-beta peptides block new protein production reveals new ways of thinking about Alzheimer's disease treatment.
"The fact that we found that protein synthesis is hugely affected by Alzheimer's disease opens up a door to let us try a variety of drugs that are already developed for other chronic progressive diseases that share this commonality of affected protein production," Yoon said.
For example, many cancer drugs are designed to block new protein synthesis to slow protein production among cancer cells. Even though the opposite effect is desired in Alzheimer's disease, these drugs may represent a starting point for a new class of Alzheimer's disease therapies, she said.
Yoon also hopes to test whether small-molecule jnk3 inhibitors could potentially improve cognitive function in Alzheimer's disease mouse models. (Source: EurekAlert! A service of AAAS and Ohio State University).
NFL players may be at higher risk of death from Alzheimer's and ALS
MINNEAPOLIS – New research shows that professional football players may be at a higher risk of death from diseases that damage the cells in the brain, such as Alzheimer's disease and ALS (also known as Lou Gehrig's disease), compared to the general U.S. population. The study is published in the September 5, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.
The study included 3,439 players with an average age of 57 from the National Football League with at least five playing seasons from 1959-1988. Researchers reviewed death certificates for causes of death from Alzheimer's disease, Parkinson's disease and ALS. At the time of the analysis, only 10 percent of the participants had passed away.
The research found that professional football players in this study were three times more likely to die as a result of diseases that damage brain cells compared to the general population. A player's risk of death from Alzheimer's disease or ALS was almost four times higher than the general population. Of the 334 who died, seven had Alzheimer's disease and seven had ALS. The risk of dying from Parkinson's disease was not significantly different than that of the general population.
To determine if these risks differed by position played, researchers divided the players into two groups: those who played non-line ("speed") positions which included quarterbacks, running backs, halfbacks, fullbacks, wide receivers, tight ends, defensive backs, safeties and linebackers, and those who played line ("non-speed") positions, which included defensive and offensive linemen. Speed position players were more than three times more likely to die from a neurodegenerative cause than non-speed position players. A total of 62 percent of the players were in speed positions.
"These results are consistent with recent studies that suggest an increased risk of neurodegenerative disease among football players," said study author Everett J. Lehman, MS, with the National Institute for Occupational Safety and Health in Cincinnati. "Although our study looked at causes of death from Alzheimer's disease and ALS as shown on death certificates, research now suggests that chronic traumatic encephalopathy (CTE) may have been the true primary or secondary factor in some of these deaths. A brain autopsy is necessary to diagnose CTE and distinguish it from Alzheimer's or ALS. While CTE is a separate diagnosis, the symptoms are often similar to those found in Alzheimer's, Parkinson's and ALS, and can occur as the result of multiple concussions."
Lehman said the study was limited by the small number of deaths in the analysis. (Source: EurekAlert! A service of AAAS and the American Academy of Neurology).
Fighting Alzheimer's before its onset
Executive function tests key to early detection of Alzheimer's, Concordia study shows
Montreal, September 10, 2012 – By the time older adults are diagnosed with Alzheimer's disease, the brain damage is irreparable. For now, modern medicine is able to slow the progression of the disease but is incapable of reversing it. What if there was a way to detect if someone is on the path to Alzheimer's before substantial and non-reversible brain damage sets in?
This was the question Erin K. Johns, a doctoral student in Concordia University's Department of Psychology and member of the Center for Research in Human Development (CRDH), asked when she started her research on older adults with mild cognitive impairment (MCI). These adults show slight impairments in memory, as well as in "executive functions" like attention, planning, and problem solving. While the impairments are mild, adults with MCI have a high risk of developing Alzheimer's disease.
"We wanted to help provide more reliable tools to identify people who are at increased risk for developing Alzheimer's so that they can be targeted for preventive strategies that would stop brain damage from progressing," says Johns.
The new study was published in the Journal of the International Neuropsychological Society and was funded by the Quebec Network for Research on Aging and the Canadian Institutes of Health Research. In it, Johns and her colleagues found that people with MCI are impaired in several aspects of executive functioning, the biggest being inhibitory control.
This ability is crucial for self-control: everything from resisting buying a candy bar at the checkout aisle to resisting the urge to mention the obvious weight gain in a relative you haven't seen in a while. Adults with MCI also had trouble with tests that measure the ability to plan and organize.
Johns and her colleagues found that all the adults with MCI they tested were impaired in at least one executive function and almost half performed poorly in all the executive function tests. This is in sharp contrast with standard screening tests and clinical interviews, which detected impairments in only 15 percent of those with MCI.
"The problem is that patients and their families have difficulty reporting executive functioning problems to their physician, because they may not have a good understanding of what these problems look like in their everyday life." says Johns. "That's why neuropsychological testing is important."
Executive function deficits affect a person's everyday life and their ability to plan and organize their activities. Even something as easy as running errands and figuring out whether to go to the drycleaners or to the supermarket can be difficult for adults with MCI. Detecting these problems early could improve patient care and treatment planning.
"If we miss the deficits, we miss out on an opportunity to intervene with the patient and the family to help them know what to expect and how to cope," says Johns. She is now conducting a follow-up study funded by the Alzheimer Society of Canada and Canadian Institutes of Health Research, along with her supervisor, Natalie Phillips, associate professor in the Department of Psychology and member of CRDH.
Johns hopes her continued research will lead to a better understanding of why these deficits start at such an early stage of Alzheimer's and what other tools could be used for earlier detection of the disease. (Source: EurekAlert! A service of AAAS and Concordia University).
Investigators identify gene linking cataracts and Alzheimer's disease
(Boston) – In a recent study, investigators at Boston University Schools of Medicine (BUSM) and Public Health (BUSPH) identified a gene linking age-related cataracts and Alzheimer's disease. The findings, published online in PLoS ONE, contribute to the growing body of evidence showing that these two diseases, both associated with increasing age, may share common etiologic factors.
Gyungah Jun, PhD, from the departments of medicine, ophthalmology and biostatistics at BUSM and BUSPH, served as the study's lead author. Lindsay A. Farrer, PhD, professor of medicine, neurology, ophthalmology, genetics & genomics, epidemiology and biostatistics and chief of the Biomedical Genetics Section at BUSM, was the study's senior author.
Using the Framingham Offspring Eye Study cohort, investigators looked at brain MRI findings on or after 10 years from the original eye exam and concluded that there was a significant correlation between a quantitative measure of cortical cataract and several Alzheimer's disease-related measures of brain degeneration, in particular volume of the temporal horn which is a brain structure that is progressively enlarged in patients with Alzheimer's disease. Another strong correlation in these same individuals, between cortical cataract formation and poorer performance on several cognitive tests administered at the time of the MRI scan, further supports this link.
With such a link not confounded by age or sex, the investigators then performed a genome-wide association study looking at nearly 190,000 single-nucleotide polymorphisms (SNPs), or DNA sequence variations. Three intronic (non-coding) SNPs in the gene encoding δ-catenin came to the fore. This protein is a key component in cell adherence and formation of cell junctional structures. Previously, δ-catenin was also implicated in brain and eye development, but not directly in either cataracts or Alzheimer's disease. To establish a more direct link of δ-catenin to Alzheimer's disease, the researchers transfected into neuronal cells δ-catenin bearing a mutation near the location of the top-associated SNPs and observed a significant and specific increase in the toxic form of amyloid β, the protein that aggregates in Alzheimer brains and thought to be central to development of the disorder. In addition, the researchers found increased deposits of δ-catenin in lens tissue obtained from autopsy-confirmed Alzheimer's cases but not from subjects lacking Alzheimer's-associated neuropathology.
"Though much work remains to be done, a link between cataracts and Alzheimer's disease supports the idea of a systemic rather than brain-limited focus for processes leading to Alzheimer's disease," said Farrer. "This study gives hope that we are moving toward earlier diagnosis and new treatment targets for this debilitating disease." (Source: EurekAlert! A service of AAAS and Boston University Medical Center).
Alzheimer's breaks brain networks' coordination
Scientists at Washington University School of Medicine in St. Louis have taken one of the first detailed looks into how Alzheimer's disease disrupts coordination among several of the brain's networks. The results, reported in The Journal of Neuroscience, include some of the earliest assessments of Alzheimer's effects on networks that are active when the brain is at rest.
"Until now, most research into Alzheimer's effects on brain networks has either focused on the networks that become active during a mental task, or the default mode network, the primary network that activates when a person is daydreaming or letting the mind wander," says senior author Beau Ances, MD, assistant professor of neurology. "There are, however, a number of additional networks besides the default mode network that become active when the brain is idling and could tell us important things about Alzheimer's effects."
Ances and his colleagues analyzed brain scans of 559 subjects. Some of these subjects were cognitively normal, while others were in the early stages of very mild to mild Alzheimer's disease. Scientists found that all of the networks they studied eventually became impaired during the initial stages of Alzheimer's.
"Communications within and between networks are disrupted, but it doesn't happen all at once," Ances says. "There's even one network that has a momentary surge of improved connections before it starts dropping again. That's the salience network, which helps you determine what in your environment you need to pay attention to."
Other networks studied by the researchers included:
the dorsal attention network, which directs attention toward things in the environment that are salient;
the control network, believed to be active in consciousness and decision-making; and
the sensory-motor network, which integrates the brain's control of body movements with sensory feedback (e.g., did the finger that just moved strike the correct piano key?).
Scientists also examined Alzheimer's effects on a brain networking property known as anti-correlations. Researchers identify networks by determining which brain areas frequently become active at the same time, but anti-correlated networks are noteworthy for the way their activities fluctuate: when one network is active, the other network is quiet. This ability to switch back-and-forth between networks is significantly diminished in participants with mild to moderate Alzheimer's disease.
The default mode network, previously identified as one of the first networks to be impaired by Alzheimer's, is a partner in two of the three pairs of anti-correlated networks scientist studied.
"While we can't prove this yet, one hypothesis is that as things go wrong in the processing of information in the default mode network, that mishandled data is passed on to other networks, where it creates additional problems," Ances says.
It's not practical to use these network breakdowns to clinically diagnose Alzheimer's disease, Ances notes, but they may help track the development of the disease and aid efforts to better understand its spread through the brain.
Ances plans to look at other markers for Alzheimer's disease in the same subjects, such as levels in the cerebrospinal fluid of amyloid beta, a major component of Alzheimer's plaques. (Source: EurekAlert! A service of AAAS and Washington University School of Medicine).
Mayo Clinic researchers identify new enzyme to fight Alzheimer's disease
JACKSONVILLE, Fla. — An enzyme that could represent a powerful new tool for combating Alzheimer's disease has been discovered by researchers at Mayo Clinic in Florida. The enzyme — known as BACE2 — destroys beta-amyloid, a toxic protein fragment that litters the brains of patients who have the disease. The findings were published online Sept. 17 in the science journal Molecular Neurodegeneration.
Alzheimer's disease is the most common memory disorder. It affects more that 5.5 million people in the United States. Despite the disorder's enormous financial and personal toll, effective treatments have not yet been found.
The Mayo research team, led by Malcolm A. Leissring, Ph.D., a neuroscientist at Mayo Clinic in Florida, made the discovery by testing hundreds of enzymes for the ability to lower beta-amyloid levels. BACE2 was found to lower beta-amyloid more effectively than all other enzymes tested. The discovery is interesting because BACE2 is closely related to another enzyme, known as BACE1, involved in producing beta-amyloid.
"Despite their close similarity, the two enzymes have completely opposite effects on beta-amyloid — BACE1 giveth, while BACE2 taketh away," Dr. Leissring says.
Beta-amyloid is a fragment of a larger protein, known as APP, and is produced by enzymes that cut APP at two places. BACE1 is the enzyme responsible for making the first cut that generates beta-amyloid. The research showed that BACE2 cuts beta-amyloid into smaller pieces, thereby destroying it, instead. Although other enzymes are known to break down beta-amyloid, BACE2 is particularly efficient at this function, the study found.
Previous work had shown that BACE2 can also lower beta-amyloid levels by a second mechanism: by cutting APP at a different spot from BACE1. BACE2 cuts in the middle of the beta-amyloid portion, which prevents beta-amyloid production.
"The fact that BACE2 can lower beta-amyloid by two distinct mechanisms makes this enzyme an especially attractive candidate for gene therapy to treat Alzheimer's disease," says first author Samer Abdul-Hay, Ph.D., a neuroscientist at Mayo Clinic in Florida.
The discovery suggests that impairments in BACE2 might increase the risk of Alzheimer's disease. This is important because certain drugs in clinical use — for example, antiviral drugs used to treat human immunodeficiency virus (HIV) — work by inhibiting enzymes similar to BACE2.
Although BACE2 can lower beta-amyloid by two distinct mechanisms, only the newly discovered mechanism — beta-amyloid destruction — is likely relevant to the disease, the researchers note. This is because the second mechanism, which involves BACE2 cutting APP, does not occur in the brain. The researchers have obtained a grant from the National Institutes of Health to study whether blocking beta-amyloid destruction by BACE2 can increase the risk for Alzheimer's disease in a mouse model of the disease. (Source: EurekAlert! A service of AAAS and the Mayo Clinic).
Scientists reverse Alzheimer's-like memory loss in animal models by blocking EGFR signaling
EGFR inhibitors used to fight cancer show surprising efficacy in fly, mouse models of beta amyloid-associated memory loss
Cold Spring Harbor, NY – A team of neuroscientists and chemists from the U.S. and China today publish research suggesting that a class of currently used anti-cancer drugs as well as several previously untested synthetic compounds show effectiveness in reversing memory loss in two animal models of Alzheimer's' disease.
CSHL Professor Yi Zhong, Ph.D., who led the research conducted in fruit flies and mice, says he and his colleagues were surprised with their results, which, he stressed, used two independent experimental approaches "the results of which clearly converged."
Specifically, the research converged on what Zhong's team suggests is a "preferred target" for treating memory loss associated with the amyloid-beta (Aβ) plaques seen in advanced Alzheimer's patients. That target is the epidermal growth factor receptor, often called by its acronym, EGFR.
Overexpression of the EGFR is a characteristic feature of certain cancers, notably a subset of lung cancers. Two targeted treatments, erlotinib (Tarceva) and gefitinib (Iressa), can dramatically, albeit transiently, reverse EGFR-positive cancers, by blocking the EGFR receptor and thus preventing its activation.
The newly published research by Zhong's team suggests that the signaling within cells that is induced by EGFR activation also plays a role in the pathology – still poorly understood – involved in Aβ-associated memory loss seen in Alzheimer's patients.
Zhong and colleagues previously had studied Aβ-associated memory loss in fruit flies with brain cells expressing the Aβ-42 peptide (a specific version of the protein, composed of 42 amino acids, seen in Alzheimer's plaques). These fruit flies are regarded as models of the illness in part because the Aβ-42 they manifest is encoded by a human gene, inserted in their genome. In behavioral experiments, such flies have been shown to suffer memory deficiencies analogous to those seen in human Alzheimer's.
In the current round of experiments, Zhong's team demonstrated that enhanced activation of EGFRs in brain cells exacerbated memory loss in the Aβ-42 fruit fly model of Alzheimer's disease. This led them to dose 3-day-old flies of the same type with the two anti-cancer EGFR inhibitors over a week's time, which was shown in behavioral tests on day 11 to prevent memory loss. The results were then confirmed in mouse models of Alzheimer's, also based on the human Aβ-42 gene.
This was remarkable, but even more so, says Zhong, because of a parallel but independent experimental process that also suggested EGFR as a drug target for Alzheimer's. This parallel process consisted of screening, by Zhong's collaborators in China, of some 2,000 synthetic compounds for activity against Aβ-induced memory loss in model fruit flies. Of these, 45 compounds showed positive results in fruit flies after two months of dosing. Nine of these were selected for testing in mouse models, of which four showed positive results after two months.
"We were amazed to find that three of these compounds – designated JKF-006, JKF-011 and JKF-027 – not only showed effective results in rescuing memory loss in the mice, but also, in test-tube-based experiments, prevented Aβ-42 from activating human EGFR," Zhong reports.
Importantly, a precise mechanism could not be conclusively demonstrated from this and related experiments. But the available evidence leads the scientists to propose in a paper appearing online today in Proceedings of the National Academy of Sciences, that reversal of memory loss occurs when clumps of beta-amyloid proteins are either prevented directly from "docking" with the human EGF receptor, or prevent phosphate groups from attaching to the receptor, a process called phosphorylation. Both hypothesized processes would prevent the initiation of the EGFR intracellular signaling cascade.
Zhong and colleagues note the uncertainty of Alzheimer's pathology. Memory loss stemming from Aβ-induced activation of EGFR "may reflect the acute toxic effects of Aβ, which might be independent of synaptic and neuronal degeneration," they note. To gain more insight, the team tested drug treatment of middle-aged mice (8 months old) with advanced memory loss during an 18-day period – some six weeks shorter than the dosing period initially shown to be effective.
"Eighteen days – the shortest dosing period we tested – was sufficient to reverse loss in these mice, although we should note that these animals had few morphological changes in the brain despite their severe memory loss when treatment began," Zhong says.
Because of the positive results they obtained in reversing memory loss in animal models, the team suggests additional testing with EGFR inhibitors be conducted, as well as testing of "behaviorally screened chemicals in treatments of Alzheimer's patients." (Source: EurekAlert! A service of AAAS and Cold Spring Harbor Laboratory).
Melatonin and exercise work against Alzheimer's in mice
Different anti-aging treatments work together and add years of life
The combination of two neuroprotective therapies, voluntary physical exercise, and the daily intake of melatonin has been shown to have a synergistic effect against brain deterioration in rodents with three different mutations of Alzheimer's disease.
A study carried out by a group of researchers from the Barcelona Biomedical Research Institute (IIBB), in collaboration with the University of Granada and the Autonomous University of Barcelona, shows the combined effect of neuroprotective therapies against Alzheimer's in mice.
Daily voluntary exercise and daily intake of melatonin, both of which are known for the effects they have in regulating circadian rhythm, show a synergistic effect against brain deterioration in the 3xTg-AD mouse, which has three mutations of Alzheimer's disease.
"For years we have known that the combination of different anti-aging therapies such as physical exercise, a Mediterranean diet, and not smoking adds years to one's life," Coral Sanfeliu, from the IIBB, explains to SINC. "Now it seems that melatonin, the sleep hormone, also has important anti-aging effects".
The experts analyzed the combined effect of sport and melatonin in 3xTg-AD mice which were experiencing an initial phase of Alzheimer's and presented learning difficulties and changes in behavior such as anxiety and apathy.
The mice were divided into one control group and three other groups which would undergo different treatments: exercise –unrestricted use of a running wheel–, melatonin –a dose equivalent to 10 mg per kg of body weight–, and a combination of melatonin and voluntary physical exercise. In addition, a reference group of mice were included which presented no mutations of the disease.
"After six months, the state of the mice undergoing treatment was closer to that of the mice with no mutations than to their own initial pathological state. From this we can say that the disease has significantly regressed," Sanfeliu states.
The results, which were published in the journal Neurobiology of Aging, show a general improvement in behavior, learning, and memory with the three treatments.
These procedures also protected the brain tissue from oxidative stress and provided good levels of protection from excesses of amyloid beta peptide and hyperphosphorylated TAU protein caused by the mutations. In the case of the mitochondria, the combined effect resulted in an increase in the analyzed indicators of improved performance which were not observed independently.
"Transferring treatments which are effective in animals to human patients is not always consistent, given that in humans the disease develops over several years, so that when memory loss begins to surface, the brain is already very deteriorated," the IIBB expert points out.
However, several clinical studies have found signs of physical and mental benefits in sufferers of Alzheimer's resulting from both treatments. The authors maintain that, until an effective pharmacological treatment is found, adopting healthy living habits is essential for reducing the risk of the disease appearing, as well as reducing the severity of its effects.
The use of melatonin, a hormone synthesized from the neurotransmitter serotonin, has positive effects which can be used for treating humans. With the approval of melatonin as a medication in the European Union in 2007, clinical testing on this molecule has been increasing. It has advocates as well as detractors, and the scientific evidence has not yet been able to unite the differing views.
According to the Natural Medicines Comprehensive Database, melatonin is probably effective in sleeping disorders in children with autism and mental retardation and in blind people; and possibly effective in case of jet-lag, sunburns and preoperative anxiety.
"However, other studies which use melatonin as medication show its high level of effectiveness," Darío Acuña-Castroviejo explains to SINC. He has been studying melatonin for several years at the Health Sciences Technology Park of the University of Granada.
The expert points out that international consensus already exists, promoted by the British Association for Psychopharmacology –also published in the Journal of Psychopharmacology in 2010–, which has melatonin as the first choice treatment for insomnia in patients above the age of 55. This consensus is now being transferred to cases of insomnia in children.
Its use in treating neurodegenerative diseases is acquiring increasing scientific support in lateral amyotrophic sclerosis, in Alzheimer's, and Duchenne muscular dystrophy.
"Even though many more studies and clinical tests are still required to assess the doses of melatonin which will be effective for a wide range of diseases, the antioxidant and anti-inflammatory properties of melatonin mean that its use is highly recommended for diseases which feature oxidative stress and inflammation," Acuña-Castroviejo states.
This is the case for diseases such as epilepsy, chronic fatigue, fibromyalgia, and even the aging process itself, where data is available pointing to the benefits of melatonin, though said data is not definitive. (Source: EurekAlert! A service of AAAS and FECYT - Spanish Foundation for Science and Technology).
Camels give President Obama's Alzheimer's plan a lift
New research in The FASEB Journal suggests that serum from animals such as camels, llamas, and alpacas could enhance brain imaging and help drugs pass through the blood-brain barrier
Bethesda, MD—President Obama's national plan to fight Alzheimer's disease just got a lift thanks to a team of international researchers whose recent discovery may lead to enhanced imaging of and improved drug delivery to the brain. A research report appearing in The FASEB Journal, describes an entirely new class of antibody discovered in camelids (camels, dromedaries, llamas, and alpacas) that is able to cross the blood-brain barrier, diffuse into brain tissue, and reach specific targets. Having such antibodies, which are naturally available, may be part of a "game changer" in the outcomes for people with brain diseases that are poorly diagnosed and treated, at best, using today's tools.
"This basic biological investigation opens new pathways toward innovative therapeutic solutions for intractable diseases such as Alzheimer's disease or brain tumors," said Pierre Lafaye, Ph.D., a researcher involved in the work from the Institut Pasteur, PF: Production de Protéines Recombinantes et d'Anticorps –Proteopole in Paris, France. "The importance of this study is the hope that this novel approach may be a useful tool in crossing the blood brain barrier for diagnostic and therapeutic purposes," added Babbette Weksler, MD, Professor of Medicine, Weill Cornell Medical College, New York, NY, another author of the study and editorial board member of The FASEB Journal.
Lafaye and colleagues studied alpacas, a member of the camelid family, and discovered an antibody naturally able to cross the blood brain barrier without chemical modification. Then, additional research showed that after these antibodies entered the brain successfully, they diffused into the brain tissue to reach a target, which in this study was astrocytes. This study shows, for the first time, an antibody penetrated into the brain in vivo, under normal physiological conditions. In addition to the obvious clinical applications of this finding, it opens the doors to new research involving the body's systems for recognizing self v. "nonself."
"Camels may be most famous for helping people travel to the outermost reaches of the desert, but soon they could be also known for helping us reach the innermost parts of our brains," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "It appears that these prized animals are far more capable of helping get to hard-to-reach places than we ever could have imagined." (Source: EurekAlert! A service of AAAS and Federation of American Societies for Experimental Biology).
Resistance to dementia may run in the family
MINNEAPOLIS – People who are free of dementia and have high levels of a protein that indicates the presence of inflammation have relatives who are more likely to avoid the disease as well, according to a new study published in the August 15, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.
"In very elderly people with good cognition, higher levels of C-reactive protein, which is related to inflammation, are associated with better memory," said study author Jeremy M. Silverman, PhD, with Mount Sinai School of Medicine in New York. "Our results found that the higher the level of this protein in the study participant, the lower the risk for dementia in their parents and siblings."
For the study, researchers identified 277 male veterans age 75 and older and free of dementia symptoms. They were given a test that measured levels of the protein. Next, the group was interviewed about 1,329 parents and siblings and whether they had dementia. A total of 40 relatives from 37 families had dementia. A secondary, independent group of 51 men age 85 and older with no dementia symptoms were given an interview about 202 relatives for dementia. Nine of the relatives had dementia.
Study investigators found that participants who had higher amounts of the protein were more than 30 percent less likely to have relatives with dementia. Similar results were found in the secondary group. Since the protein levels were not associated with years of education, marital status, occupation and physical activity, these factors could not account for the lower risks seen.
"This protein is related to worse cognition in younger elderly people. Thus, for very old people who remain cognitively healthy, those with a high protein level may be more resistant to dementia," said Silverman. "Our study shows that this protection may be passed on to immediate relatives." (Source: EurekAlert! A service of AAAS and the American Academy of Neurology).
Over 65s at increased risk of developing dementia with benzodiazepine
Research: Benzodiazepine use and risk of dementia: Prospective population based study
Research: Benzodiazepine use and risk of dementia: prospective population based study
Patients over the age of 65 who begin taking benzodiazepine (a popular drug used to treat anxiety and insomnia) are at an approximately 50% increased risk of developing dementia within 15 years compared to never-users, a study published today on bmj.com suggests.
The authors say that "considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects indiscriminate widespread use should be cautioned against".
Benzodiazepine is a widely prescribed drug for the over 65s in many countries: 30% of this age group in France, 20% in Canada and Spain, 15% in Australia. Although less widespread in the UK and US it is still very widely used and many individuals take this drug for years despite guidelines suggesting it should be limited to a few weeks. Previous studies have found an increased risk of dementia, but others have been non-conclusive.
Researchers from France therefore carried out a study on 1063 men and women (average age 78) in France who were all free of dementia at the start. The study started in 1987 and follow-up was 20 years. The researchers used the first 5 years to identifying the factors leading to benzodiazepine initiation and evaluated then the association between new use of this drug and the development of dementia. They also assessed the association between further benzodiazepine initiation during the follow-up period and risk of subsequent dementia. Rates were adjusted for many factors potentially affecting dementia, such as age, gender, educational level, marital status, wine consumption, diabetes, high blood pressure, cognitive decline, and depressive symptoms.
95 out of the 1063 patients started taking benzodiazepine during the study. 253 (23.8%) cases of dementia were confirmed, 30 in benzodiazepine users and 223 in non-users. New initiation of the drug was associated with shorter dementia-free survival.
In absolute numbers, the chance of dementia occurring was 4.8 per 100 person years in the exposed group compared to 3.2 per 100 person years in the non-exposed group. A "person year" is a statistical measure representing one person at risk of development of a disease during a period of one year.
The authors say that although benzodiazepine remains useful for treating anxiety and insomnia, there is increasing evidence that its use may induce adverse outcomes in the elderly such as serious falls and fall-related fractures and this study may add dementia to the list. They say that their data add to the accumulating evidence that the use of benzodiazepines is associated with increased risk of dementia and, if true, that this "would constitute a substantial public health concern". Therefore, taken the evidence of potential adverse effects into account, physicians should assess expected benefits, limit prescriptions to a few weeks, and uncontrolled use should be cautioned against. They conclude that further research should "explore whether use of benzodiazepine in those under 65 is also associated with increased risk of dementia and that mechanisms need to be explored explaining the association" (Source: EurekAlert! A service of AAAS and the British Medical Journal).
Scientists report promising new direction for cognitive rehabilitation in the elderly
Findings published in Restorative Neurology and Neuroscience
Amsterdam, NL, August 20, 2012 – Research has found that declines in temporal information processing (TIP), the rate at which auditory information is processed, underlies the progressive loss of function across multiple cognitive systems in the elderly, including new learning, memory, perception, attention, thinking, motor control, problem solving, and concept formation. In a new study, scientists have found that elderly subjects who underwent temporal training improved not only the rate at which they processed auditory information, but also in other cognitive areas. The study is published in the current issue of Restorative Neurology and Neuroscience.
"Our study showed for the first time significant benefits of temporal training on broad aspects of cognitive function in the elderly. The results were long-lasting, with effects confirmed 18 months after the training," says lead investigator Elzbieta Szelag, Professor, Head of Laboratory of Neuropsychology, Nencki Institute of Experimental Biology (www.nencki.gov.pl), and Warsaw School of Social Sciences and Humanities (www.swps.pl), Warsaw, Poland.
Thirty subjects between 65 and 75 years of age were randomly assigned to three groups. One group received temporal training using Fast ForWord Language® (FFW), a program comprised of several computer games designed to improve memory, attention, and sequencing abilities. The program was developed to help children who have trouble reading, writing, and learning. The second group participated in non-temporal training by playing common computer games. The third group, the control, underwent no training.
Prior to the training, all of the subjects went through a number of tests to measure their cognitive functioning. Two tasks assessed TIP by measuring sequencing abilities. Specifically, at which inter-stimulus-interval subjects could identify the order of two stimuli presented in rapid sequence, i.e. which of two tones was higher or lower, or whether they heard a sound in the right or left ear first. Three aspects of attention were assessed: the ability to sustain attention over a longer period of time (vigilance), the ability to pay attention to multiple processes (divided attention), and the ability to maintain a high level of attention in anticipation of a test stimulus (alertness). Short-term memory was assessed with tests to evaluate working memory span, the ability to match complex patterns, and the ability to recognize a pattern seen earlier.
Each subject in the temporal training group started with exercises from the basic module of FFW. When they reached 100% complete for each exercise, they moved onto an intermediate program, and then an advanced program. They trained for an hour a day, four days a week, for eight weeks. The non-temporal training group played computer games such as Solitaire or Internet games such as Mahjong for the same amount of time. The control group received no training but was tested before and after the eight-week period.
At the end of the training period, cognitive functioning was re-assessed. Prior to training, no significant differences were found among the three groups. After the training, improved temporal information processing was found on the tone task in the temporal training group. It was accompanied by improvements in some aspects of attention and short-term memory. In contrast, the non-temporal training group's attentional and memory resources scores remained at the pre-training level, while only the second measure of temporal information processing improved. Changes in the control group were nonsignificant.
The temporal training group was tested again 18 months after the training completion. The positive effects remained stable. TIP, divided attention, matching complex patterns, and working memory span remained at a similar level as in the post-training assessment. Although vigilance of attention declined from the post-training assessment, for all measures the results were not worse than in the pre-training assessment. "Although FFW does not train other cognitive functions directly, attention and short-term memory resources were necessary to perform the training tasks correctly," explain Professor Szelag and Dr Skolimowska. "To succeed in the FFW games, the temporal skills had to be accompanied by efficient basic cognitive processes."
Professor Szelag concludes, "These results show a new impact of temporal training on age-related cognitive decline in the senior population. Moreover, they foster a greater understanding of the relationships between timing and cognition, and they show new possibilities for the application of temporal training." On the basis of these results the Laboratory of Neuropsychology has recently initiated an innovative rehabilitation computer program that addresses improvement of a broad range of cognitive functions in children and adults. (Source: EurekAlert! A service of AAAS and IOS Press).