Abstract
Study finds nicotine patches may help improve memory loss in older adults
Wearing a nicotine patch may help improve memory loss in older adults with mild cognitive impairment, according to a study published today in Neurology, the medical journal of the American Academy of Neurology.
The study looked at individuals with mild cognitive impairment (MCI), the stage between normal aging and dementia when others begin to notice that an individual is developing mild memory or thinking problems. Many older adults with MCI go on to develop Alzheimer's disease.
The study looked at 74 non-smokers with MCI and an average age of 76. Half of the patients were given a nicotine patch of 15 mg a day for six months and half received a placebo. The study was designed so neither the participants nor the investigators knew which group received the nicotine patch.
Paul Newhouse, M.D., professor of Psychiatry and director of the Center for Cognitive Medicine at Vanderbilt University Medical Center, who authored the study, said the results of the study should not be viewed as an endorsement of smoking or of nicotine for normal individuals. “What we and others have shown is that nicotine doesn't do much for memory and attention in the normal population, but it does do something for those whose cognitive function is already impaired.”
“People with memory loss should not start smoking or using nicotine patches by themselves because there are harmful effects of smoking and a medication such as nicotine should only be used with a doctor's supervision,” Newhouse said. “But this study provides strong justification for further research into the use of nicotine for people with early signs of memory loss which may help us determine whether benefits persist over long periods of time and provide meaningful improvement.”
Newhouse said nicotine is a “fascinating drug with interesting properties.” The effects of nicotine are dependent on the initial state of a person's cognitive functioning, he said. “If you're already functioning fine, but slip down the hill, nicotine will push you back up toward the top. A little bit of the drug makes poor performers better. Too much, and it makes them worse again, so there's a range. The key issue is to find the sweet spot where it helps.”
The study showed evidence of improvement across multiple cognitive tests for attention memory, speed of processing and consistency of processing. For example, after 6 months of treatment, the nicotine-treated group regained 46 percent of normal performance for age on long-term memory, whereas the placebo group worsened by 26 percent over the same time period. One area that didn't show significant improvement was that of “global impression,” which means a health care provider didn't observe the patient was any better or any worse.
Newhouse said that future study is needed. “We need to do a much longer and larger study, to see if we can make a significant impact on the process of change.”
Nicotine stimulates receptors in the brain that are important for thinking and memory and may have neuroprotective effects. People with Alzheimer's disease lose some of those receptors.
Newhouse said the future of nicotinic treatment is to try to identify earlier stages at which treatment can be applied, to see if it changes the trajectory of those who already have evidence of memory loss. “I don't think it's going to become a treatment for Alzheimer's disease by itself. That would be like trying to rebuild a house after a fire when the fire's still going. You need to prevent the fire. The holy grail would be changing the deterioration curve.”
Those in the study group receiving the nicotine patch experienced only minor side effects like nausea and dizziness, similar to what a person would experience when smoking a cigarette for the first time, Newhouse said. Those on the nicotine patch also experienced mild weight loss, not surprising since nicotine is an appetite suppressant. There were also no withdrawal symptoms reported when the study participants stopped using the nicotine patch.(Source: EurekAlert! A service of AAAS and Vanderbilt University Medical Center).
Use it or lose it: Mind games help healthy older people too
Cognitive training including puzzles, handicrafts and life skills are known to reduce the risk, and help slow down the progress, of dementia amongst the elderly. A new study published in BioMed Central's open access journal BMC Medicine showed that cognitive training was able to improve reasoning, memory, language and hand eye co-ordination of healthy, older adults.
It is estimated that by 2050 the number of people over 65 years old will have increased to 1.1 billion worldwide, and that 37 million of these will suffer from dementia. Research has already shown that mental activity can reduce a person's risk of dementia but the effect of mental training on healthy people is less well understood. To address this researchers from China have investigated the use of cognitive training as a defence against mental decline for healthy older adults who live independently.
To be recruited onto the trial participants had to be between 65 and 75 years old, and have good enough eyesight, hearing, and communication skills, to be able to complete all parts of the training. The hour long training sessions occurred twice a week, for 12 weeks, and the subjects were provided with homework. Training included a multi-approach system tackling memory, reasoning, problem solving, map reading, handicrafts, health education and exercise, or focussing on reasoning only. The effect of booster training, provided six months later, was also tested.
The results of the study were positive. Profs Chunbo Li and Wenyuan Wu who led the research explained, “Compared to the control group, who received no training, both levels of cognitive training improved mental ability, although the multifaceted training had more of a long term effect. The more detailed training also improved memory, even when measured a year later and booster training had an additional improvement on mental ability scores.”
This study shows that cognitive training therapy may prevent mental decline amongst healthy older people and help them to continue independent living longer in their advancing years. (Source: EurekAlert! A service of AAAS and BioMed Central).
A new test might facilitate diagnosis and drug development for Alzheimer's disease
An international team of researchers have developed a new method for measurement of aggregated beta-amyloid – a protein complex believed to cause major nerve cell damage and dysfunction in Alzheimer's disease. The new method might facilitate diagnosis and detection as well as development of drugs directed against aggregated beta-amyloid.
Alzheimer's disease (AD) is the most common cause of memory decline and dementia. According to the Alzheimer World Report 2011, today around 36 million people suffer from Dementia (around 20 - 25 million are Alzheimer's patients). These numbers will dramatically increase with the aging populations over the next few decades. For the year 2050 the expected number of dementia patients will be 115 - 200 million (70 – 150 million Alzheimer's cases). It is therefore important to develop new therapies and diagnostic methods to detect and treat this complex chronic neurodegenerative brain disease.
Alzheimer's disease is characterized by aggregates in the brain, containing a protein called beta-amyloid. The neuropathology of Alzheimer's disease has recently been linked to the neurotoxic amyloid-β (Aβ) oligomers. The crucial role of Aβ oligomers in the early events of AD is experimentally underlined. Several recent results suggest that those oligomers may cause the death of neurons and neurological dysfunctions relevant to memory. Furthermore Aβ oligomers levels are increased in brain and cerebrospinal fluid samples from people with Alzheimer's disease. This reflects the potential of Aβ oligomers as a marker for the early diagnosis of the disease.
An international team of scientists from Germany, Sweden and the U.S. have used a new method to quantify soluble variants of aggregated beta-amyloid (Aβ oligomers) in cerebrospinal fluid by flow cytometry. “We found that patients with a greater number of Aβ oligomers in the cerebrospinal fluid had a more pronounced disease,” says Dr. Alexander Navarrete Santos (the developer of this method and now employee of the Research Laboratory of the University of Halle, Department of Cardiothoracic Surgery), and first author of the study.
He analyzed the cerebrospinal fluid of 30 neurological patients, including 14 Alzheimer's patients. “These samples provided from leading expert academic memory clinics in Germany and Sweden are of the best quality and are highly characterized in order to provide robust and reliable results on promising novel biomarker candidates”, Professor Harald Hampel of Frankfurt University, a lead investigator comments.
“Because of the limited number of samples, however, further study is needed to confirm the results,” said Dr. Oskar Hansson of Lund University. The study was an international cooperation with the University of California in the U.S., the Goteborg and Malmö Universities from Sweden and the University of Frankfurt in Germany.
The test might not only be used for the early detection of AD but can also be used when developing new and effective therapies for AD. A decline in the number of Aβ oligomers in cerebrospinal fluids could be a hint for the effectiveness of new drug therapies. (Source: EurekAlert! A service of AAAS and IOS Press).
Brain insulin resistance contributes to cognitive decline in Alzheimer's disease
PHILADELPHIA – Insulin resistance in the brain precedes and contributes to cognitive decline above and beyond other known causes of Alzheimer's disease, according to a new study by researchers from the Perelman School of Medicine at the University of Pennsylvania. Insulin is an important hormone in many bodily functions, including the health of brain cells. The team identified extensive abnormalities in the activity of two major signaling pathways for insulin and insulin-like growth factor in non-diabetic people with Alzheimer's disease. These pathways could be targeted with new or existing medicines to potentially help resensitize the brain to insulin and possibly slow down or even improve cognitive decline.
This is the first study to directly demonstrate that insulin resistance occurs in the brains of people with Alzheimer's disease. The study is now online in the Journal of Clinical Investigation.
“Our research clearly shows that the brain's ability to respond to insulin, which is important for normal brain function, is going offline at some point. Insulin in the brain not only modulates glucose uptake, but also promotes the health of brain cells – their growth, survival, remodeling, and normal functioning. We believe that brain insulin resistance may be an important contributor to the cognitive decline associated with Alzheimer's disease,” said senior author, Steven E. Arnold, MD, professor of Psychiatry and Neurology. Arnold is also the director of the Penn Memory Center, a National Institute on Aging-designated Alzheimer's Disease Core Center. “If we can prevent brain insulin resistance from occurring, or re-sensitize brain cells to insulin with any of the currently available insulin-sensitizing diabetes medicines, we may be able to slow down, prevent, or perhaps even improve cognitive decline.
The risk of developing Alzheimer's disease is increased by 50 percent in people with diabetes. Type 2 diabetes is due to insulin resistance and accounts for 90 percent of all diabetes. The defining clinical feature of Type 2 diabetes (and Type 1 “juvenile” diabetes) is hyperglycemia - high levels of sugar in the blood – but there is no evidence that the brain in Alzheimer's is hyperglycemic. Insulin acts differently in the brain than in the rest of the body. Researchers found that insulin resistance of the brain occurs in Alzheimer's disease independent of whether someone has diabetes, by excluding people with a history of diabetes from this study.
The investigators used samples of postmortem brain tissue from non-diabetics who had died with Alzheimer's disease, stimulated the tissue with insulin, and measured how much the insulin activated various proteins in the insulin-signaling pathways. There was less insulin activation in Alzheimer's cases than in tissue from people who had died without brain disease. Other proteins linked to insulin action in the brain were abnormal in Alzheimer's disease samples. These abnormalities were highly correlated with episodic memory and other cognitive disabilities in the Alzheimer's disease patients.
In tissue from people with Alzheimer's disease and mild cognitive impairment (MCI), researchers found that changes to a protein called insulin receptor substrate-1 (IRS-1 pS636/639 and pS616) in brain cells were linked to the severity of memory impairments regardless of age, sex, diabetes history, or apolipoprotein E (APOE) gene status. Levels of IRS-1 were also significantly associated with, but not likely to affect, the presence of amyloid beta plaques and neurofibrillary tangles, the signature markers of Alzheimer's disease. This suggests that insulin resistance contributes to cognitive decline independent of the classical pathology of Alzheimer's disease.
Researchers noted that three insulin-sensitizing medicines are already approved by the FDA for treatment of diabetes. These drugs readily cross the blood-brain barrier and may have therapeutic potential to correct insulin resistance in Alzheimer's disease and MCI. “Clinical trials would need to be conducted to determine the impact the drugs have on Alzheimer's disease and MCI in non-diabetic patients,” said Dr. Arnold. (Source: EurekAlert! A service of AAAS and the University of Pennsylvania School of Medicine).
New study supports view that Lewy bodies are not the primary cause of cell death in PD
Amsterdam, NL, January 9, 2011 – The pathology of Parkinson's disease is characterized by a loss of dopamine-producing neurons in the pars compacta of the substantia nigra (SN), an area of the brain associated with motor control, along with the development of α-synuclein (αS) protein in the form of Lewy bodies (LB) in the neurons that survive. The spread of LB pathology is thought to progress along with the clinical course of Parkinson's disease, although recent studies suggest that they are not the toxic cause of cell death. A new study published in The Journal of Parkinson's Disease finds no support for a primary pathogenic role of LBs, as neither their distribution nor density was associated with the severity of nigral cell loss.
“We investigated the relationship between nigral dopaminergic cell loss, distribution and density of α-synuclein immunoreactive LBs, and the duration of motor symptoms in 97 patients with Parkinson's disease,” explains lead investigator Andrew J. Lees, MD, of Queen Square Brain Bank for Neurological Disorders and the Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK. “Despite the reasonably close correlation between neuronal density in SN and severity of bradykinesia and rigidity in Parkinson's disease, our results suggest that nigral cell loss is gradual and there is considerable variability, which may explain the clinical heterogeneity.”
Researchers confirmed that both neuronal number and density in SN in Parkinson's disease decrease over time. The density of nigral neurons was estimated to decrease by 2% each year after confirmation of the clinical diagnosis of Parkinson's disease, but showed marked heterogeneity across patients. Some patients with longer duration of illness still had a significant number of preserved nigral neurons at the time of death. An average of 15% of surviving nigral neurons contained LBs -+and the age-adjusted proportion of LB-bearing neurons appeared relatively stable through the disease duration. “This could be explained by a passive `one-pass' phenomenon where the LBs appear at the beginning of the disease and then decrease at the same rate as nigral neurons are lost, or alternatively that a dynamic `turnover' occurs with some LBs continuously produced and destroyed at the same rate,” explains Dr. Lees.
Nigral neuron density was unrelated to the Braak PD stage of the disease (i.e. distribution of LBs in the brain) or to cortical LB densities. “In our view, the fact that neither the widespread regional distribution of LBs nor increased cortical LB densities were found directly linked with pars compacta nigral cell loss lends support to the view that they are not the primary cause of the pathological process leading to cell death in vulnerable regions in the brain in Parkinson's disease,” concludes Dr. Lees. (Source: EurekAlert! A service of AAAS and IOS Press).
Chronic stress spawns protein aggregates linked to Alzheimer's
Repeated stress triggers the production and accumulation of insoluble tau protein aggregates inside the brain cells of mice, say researchers at the University of California, San Diego School of Medicine in a new study published in the March 26 Online Early Edition of the Proceedings of the National Academy of Sciences.
The aggregates are similar to neurofibrillary tangles or NFTs, modified protein structures that are one of the physiological hallmarks of Alzheimer's disease. Lead author Robert A. Rissman, PhD, assistant professor of neurosciences, said the findings may at least partly explain why clinical studies have found a strong link between people prone to stress and development of sporadic Alzheimer's disease (AD), which accounts for up to 95 percent of all AD cases in humans.
“In the mouse models, we found that repeated episodes of emotional stress, which has been demonstrated to be comparable to what humans might experience in ordinary life, resulted in the phosphorylation and altered solubility of tau proteins in neurons,” Rissman said. “These events are critical in the development of NFT pathology in Alzheimer's disease.”
The effect was most notable in the hippocampus, said Rissman, a region of the brain linked to the formation, organization and storage of memories. In AD patients, the hippocampus is typically the first region of the brain affected by tau pathology and the hardest-hit, with substantial cell death and shrinkage.
Not all forms of stress are equally threatening. In earlier research, Rissman and colleagues reported that acute stress – a single, passing episode – does not result in lasting, debilitating long lasting changes in accumulation of phosphorylated tau. Acute stress-induced modifications in the cell are transient, he said, and on the whole, probably beneficial.
“Acute stress may be useful for brain plasticity and helping to facilitate learning. Chronic stress and continuous activation of stress pathways may lead to pathological changes in stress circuitry. It may be too much of a good thing.” As people age, perhaps their neuronal circuits do too, he said, becoming less robust and perhaps less capable of completely rebounding from the effects of stress.
“Age is the primary, known risk factor for Alzheimer's disease. It may be that as we age, our neurons just aren't as plastic as they once were and some succumb.”
The researchers observed that stress cues impacted two key corticotropin-releasing factor receptors, suggesting a target for potential therapies. Rissman noted drugs already exist and are in human trials (for other conditions) that modulate the activity of these receptors.
“You can't eliminate stress. We all need to be able to respond at some level to stressful stimuli. The idea is to use an antagonist molecule to reduce the effects of stress upon neurons. The stress system can still respond, but the response in the brain and hippocampus would be toned down so that it doesn't result in harmful, permanent damage.” (Source: EurekAlert! A service of AAAS and the University of California - San Diego).
Same Genes Linked to Early- and Late-Onset Alzheimer’s
The same gene mutations linked to inherited, early-onset Alzheimer’s disease have been found in people with the more common late-onset form of the illness.
The discovery by researchers at Washington University School of Medicine in St. Louis may lead doctors and researchers to change the way Alzheimer’s disease is classified.
They report their findings Feb. 1 in the online journal PLoS One (Public Library of Science).
“We probably shouldn’t think of early-onset disease as inherited and late-onset as sporadic because sporadic cases and familial clustering occur in both age groups,” says senior investigator Alison M. Goate, DPhil. “I think it’s reasonable to assume that at least some cases among both early- and late-onset disease have the same causes. Our findings suggest the disease mechanism can be the same, regardless of the age at which Alzheimer’s strikes. People who get the disease at younger ages probably have more risk factors and fewer protective ones, while those who develop the disease later in life may have more protective factors, but it appears the mechanism may be the same for both.”
The researchers used next-generation DNA sequencing to analyze genes linked to dementia. They sequenced the APP (amyloid precursor protein) gene, and the PSEN1 and PSEN2 (presenilin) genes. Mutations in those genes have been identified as causes of early-onset Alzheimer’s disease. They also sequenced the MAPT (microtubule associated protein tau) gene and GRN (progranulin) gene, which have been associated with inherited forms of another illness involving memory loss called frontotemporal dementia.
“We found an increase in rare variants in the Alzheimer’s genes in families where four or more members were affected with late-onset disease,” says Goate, the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry, professor of neurology, of genetics and co-director of the Hope Center Program on Protein Aggregation and Neurodegeneration. “Changes in these genes were more common in Alzheimer’s cases with a family history of dementia, compared to normal individuals. This suggests that some of these gene variants are likely contributing to Alzheimer’s disease risk.”
The study also found mutations in the MAPT and GRN genes in some Alzheimer’s patients, suggesting they had been incorrectly diagnosed as having Alzheimer’s disease when they instead had frontotemporal dementia.
Goate and her colleagues studied the five genes in members of 440 families in which at least four individuals per family had been diagnosed with Alzheimer’s disease. They found rare variants in key Alzheimer’s-related genes in 13 percent of the samples they analyzed.
“Of those rare gene variants, we think about 5 percent likely contribute to Alzheimer’s disease,” says first author Carlos Cruchaga, PhD, assistant professor of psychiatry. “That may not seem like a lot, but so many people have the late-onset form of Alzheimer’s that even a very small percentage of patients with changes in these genes could represent very large numbers of affected individuals.”
Goate, who in 1991 was the first scientist to identify a mutation in the APP gene linked to inherited, early-onset Alzheimer’s disease, now wants to look closely at families with multiple cases of Alzheimer’s but no mutations in previously identified Alzheimer’s genes. She says it’s likely they carry mutations in genes that scientists don’t yet know about. And she believes that new sequencing techniques could speed the discovery of these genes. In fact, the researchers say a study like this would have been impossible only a few years ago.
“With next-generation sequencing technology, it’s now possible to sequence all of these genes at the same time,” Cruchaga says. “One reason we didn’t do this study until now is that 15 to 20 years ago when these genes were first identified, it would have taken years to sequence each gene individually.”
Cruchaga and Goate say the new technology and their new findings suggest that it may be worthwhile to sequence these genes in people with a strong family history of Alzheimer’s disease.
“We would like to see physicians who treat patients with late-onset disease ask detailed questions about family history,” Goate says. “I’m sure many probably do that already, but in those families with very strong histories, it’s not unreasonable to think about screening for genetic mutations.”
She says such screenings also may weed out people thought to have Alzheimer’s disease who actually have changes in genes related to frontotemperal dementia.
Both Goate and Cruchaga agree that one result of their discovery that the same genes can be connected with both early- and late-onset forms of Alzheimer’s disease may be changes in the way the disease is classified.
“It’s always been somewhat arbitrary, figuring out where early-onset ends and late-onset begins,” Goate says. “So I no longer look at early- and late-onset disease as being different illnesses. I think of them as stages along a continuum.” (Source: Newswise and Washington University in St. Louis).
Advance Toward an Imaging Agent for Diagnosing Alzheimer’s Disease
Scientists are reporting development and initial laboratory tests of an imaging agent that shows promise for detecting the tell-tale signs of Alzheimer’s disease (AD) in the brain — signs that now can’t confirm a diagnosis until after patients have died. Their report appears in the journal ACS Medicinal Chemistry Letters.
Masahiro Ono and colleagues explain that no proven laboratory test or medical scan now exists for AD, which is claiming an increasingly heavy toll with the graying of the world’s population. Patients now get a diagnosis of AD based on their medical history and symptoms, and symptoms like memory loss often are identical to those of normal aging. Currently, the only definitive way to diagnose AD involves an autopsy with examination of brain samples for the presence of the clumps and tangles of abnormal protein that occur in the disease.
The scientists describe the synthesis and lab testing of a new imaging agent (called FPPDB), which bound tightly to ß-amyloid plaques and neurofibrillary tangles — signs of AD — in human brain samples. In normal laboratory mice, which served as stand-ins for humans, FPPDB stayed in the body long enough for a PET scan (a sophisticated medical imaging technique). With further development, the imaging agent may allow early AD diagnosis in humans, the scientists indicate. (Source: Newswise and the American Chemical Society).
Alzheimer's Drug Candidate May be First to Prevent Disease Progression
La Jolla – A new drug candidate may be the first capable of halting the devastating mental decline of Alzheimer's disease, based on the findings of a study published today in PLoS one.
When given to mice with Alzheimer's, the drug, known as J147, improved memory and prevented brain damage caused by the disease. The new compound, developed by scientists at the Salk Institute for Biological Studies, could be tested for treatment of the disease in humans in the near future.
“J147 enhances memory in both normal and Alzheimer's mice and also protects the brain from the loss of synaptic connections,” says David Schubert, the head of Salk's Cellular Neurobiology Laboratory, whose team developed the new drug. “No drugs on the market for Alzheimer's have both of these properties.”
Although it is yet unknown whether the compound will prove safe and effective in humans, the Salk researchers' say their results suggest the drug may hold potential for treatment of people with Alzheimer's.
As many as 5.4 million Americans suffer from Alzheimer's, according to the National Institutes of Health. More than 16 million will have the disease by 2050, according to Alzheimer's Association estimates, resulting in medical costs of over $1 trillion per year.
The disease causes a steady, irreversible decline in brain function, erasing a person's memory and ability to think clearly until they are unable to perform simple tasks such as eating and talking, and it is ultimately fatal. Alzheimer's is linked to aging and typically appears after age 60, although a small percentage of families carry a genetic risk for earlier onset. Among the top ten causes of death, Alzheimer's is the only one without a way to prevent, cure or slow disease progression.
Scientists are unclear what causes Alzheimer's, which appears to emerge from a complex mix of genetics, environment and lifestyle factors. So far, the drugs developed to treat the disease, such as Aricept, Razadyne and Exelon, only produce fleeting memory improvements and do nothing to slow the overall course of the disease.
To find a new type of drug, Schubert and his colleagues bucked the trend within the pharmaceutical industry of focusing exclusively on the biological pathways involved in the formation of amyloid plaques, the dense deposits of protein that characterize the disease. To date, Schubert says, all amyloid-based drugs have failed in clinical trials.
Instead, the Salk team developed methods for using living neurons grown in laboratory dishes to test whether or not new synthetic compounds were effective at protecting the brain cells against several pathologies associated with brain aging. Based on the test results from each chemical iteration of the lead compound, which was originally developed for treatment of stroke and traumatic brain injury, they were able to alter its chemical structure to make a much more potent Alzheimer's drug.
“Alzheimer's is a complex disease, but most drug development in the pharmaceutical world has focused on a single aspect of the disease--the amyloid pathway,” says Marguerite Prior, a research associate in Schubert's lab, who led the project along with Qi Chen, a former Salk postdoctoral researcher. “In contrast, by testing these compounds in living cell cultures, we can determine what they do against a range of age-related problems and select the best candidate that addresses multiple aspects of the disease, not just one.”
With a promising compound in hand, the researchers shifted to testing J147 as an oral medication in mice. Working with Amanda Roberts, a professor of molecular neurosciences at The Scripps Research Institute, they conducted a range of behavioral tests that showed that the drug improved memory in normal rodents.
The Salk researchers went on to show that it prevented cognitive decline in animals with Alzheimer's and that mice and rats treated with the drug produced more of a protein called brain-derived neurotrophic factor (BDNF), a molecule that protects neurons from toxic insults, helps new neurons grow and connect with other brain cells, and is involved in memory formation.
Because of the broad ability of J147 to protect nerve cells, the researchers believe that it may also be effective for treating other neurological disorders, such as Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS), as well as stroke. (Source: Newswise and the Salk Institute for Biological Studies).