7.26.2012
Exercise May Help Improve Cognitive Function in Older Adults
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You may not be able to stop the aging process, but you can at least do something to prevent your brain from deteriorating. Four new studiespresented at the Alzheimer’s Association International Conference in Vancouver suggest that exercise may help improve cognitive skills, even in people over the age of 65.
In one study, researchers assigned 120 inactive adults to a year-long exercise regimen. Some participated in moderate-intensity walks, while others joined a stretching-toning program. By using Magentic Resonance Imaging (MRI) to scan the brain, researchers found that those who did a year of moderate-intensity walks had better memory and increased volume in the hippocampus, which is important for processing memory.
The second study involved patients diagnosed with mild cognitive impairment (MCI). In the study led by Dr. Hiroyuki Shimada of the National Center for Geriatrics & Gerontology in Japan, 47 adults between the ages of 65 and 93 were assigned to either a multifaceted exercise program or a no-exercise group for a year. The multifaceted program involved aerobic exercise, strength exercise and balance training. Those who weren’t involved in the exercise program simply took health classes. At the end of the study, those who were part of the exercise program showed improvements in memory and language skills.
In the study conducted by researchers at the University of British Columbia in Vancouver, women aged 70 to 80 (also with MCI) were divided into three groups: resistance training, aerobic training, or balance-and-tone training. The participants exercised two times a week for six months. After half a year, researchers found that those who did strength training reaped the most benefits. They did better on tests assessing attention, memory, and higher-order brain functions like conflict resolution. Women in strength training also showed increased function in three brain regions involved with memory.
The last study divided 155 community-dwelling women between the ages of 65 and 75 into two groups; one would do resistance training, and the other would do balance-and-tone training. After one year, researchers found that all of the women had improved memory function, but that those with better cognitive function in the first place did remarkably well under resistance training.
In the study conducted by researchers at the University of British Columbia in Vancouver, women aged 70 to 80 (also with MCI) were divided into three groups: resistance training, aerobic training, or balance-and-tone training. The participants exercised two times a week for six months. After half a year, researchers found that those who did strength training reaped the most benefits. They did better on tests assessing attention, memory, and higher-order brain functions like conflict resolution. Women in strength training also showed increased function in three brain regions involved with memory.
The last study divided 155 community-dwelling women between the ages of 65 and 75 into two groups; one would do resistance training, and the other would do balance-and-tone training. After one year, researchers found that all of the women had improved memory function, but that those with better cognitive function in the first place did remarkably well under resistance training.
These four studies only serve to reiterate the importance of exercise. Strength training, in particular, seems to be the most effective.
Labels: hiroyuki-shimada, MCI, university-of-british-columbia
// posted by neurofuture10:08 AM permanent link
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7.25.2012
Rodent Study Suggests Low-Dose Pioglitazone May Improve Cognitive Function in Alzheimer's Patients
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Researchers at Takeda and Zinfandel Pharmaceuticals have found that the brain functional connectivity of rats shows better improvement with low doses of pioglitazone than with higher doses of the drug. The data, presented at the Alzheimer's Association International Conference this week, suggest that the drug – currently sold by Takeda as a treatment for type 2 diabetes under the brand name Actos – may be given to Alzheimer's patients in clinical trials at much lower doses than are administered to diabetics, thereby reducing their risk of experiencing significant adverse reactions.
The dose finding study brings the team a step closer toward a Phase III trial to test pioglitazone's ability to delay the onset of mild cognitive impairment in a genetically selected subset of patients deemed to be at high risk for developing Alzheimer's disease within five years.
In the study, called BOLD, researchers led by Karen Asin of Takeda looked at the pharmacokinetics and pharmacodynamics of pioglitazone in rats to assess if it increased glucose and oxygen utilization in certain regions of the brain. "Using a method for looking at dose determination for getting a brain effect, the surprising result is that the lower doses were better than the higher doses of [pioglitazone]," Allen Roses, professor of neurology at Duke University's Department of Medicine, Zinfandel CEO, and an author in the BOLD trial, told PGx Reporter.
In the BOLD study, Roses and colleagues gave rats doses of pioglitazone that would be equivalent to human doses of 1.5 mg to 12 mg. "Those doses are well below the doses that were used for the 22 million man years of treatment of diabetes," said Roses. The Actos label recommends starting diabetes patients at 15 mg/day and increasing the dosage as needed up to 45 mg/day.
Rats in the BOLD trial were treated at baseline with citric acid and then either continued to receive citric acid or one of four doses of pioglitazone (0.04, 0.08, 0.16, or 0.32 mg/kg/day) for seven days. One group of control and pioglitazone-treated rats received MRI scans after the second day of dosing, while all rats in the study received MRI scans after the seventh day. The researchers analyzed 57 regions of interest in the rats' brains.
Roses and his team found that 17 brain functional connections were significantly affected in the rats after they received pioglitazone for seven days. The affected regions of the brain showed improved functional connectivity after two days of receiving the drug. Compared to the rats in the control arm, two functional connections demonstrated "significant changes" in animals treated with 0.8 mg/kg/day of pioglitazone, which translates to a 3 mg/day dose in humans.
Based on these results, Asin et al. concluded in a poster presented at AAIC that pioglitazone doses that are lower than those used to treat type 2 diabetes can lead to positive changes in brain functioning in non-diabetic rats.
"Although the exact molecular mechanisms through which pioglitazone provides neuroprotection are unknown, pioglitazone stimulates mitochondrial biogenesis, improves metabolic function, reduces inflammation, and elicits beneficial changes in Aβ homeostasis through agonism of PPARγ receptors located in the brain and periphery," the investigators wrote in the abstract. Results from the BOLD study "support the suggestion that thiazolidinediones may be a useful approach for addressing cognitive deficits associated with neurodegenerative diseases, including Alzheimer's disease."
The BOLD study is part of Takeda's development program for low-dose pioglitazone as a treatment to delay the onset of mild cognitive impairment from Alzheimer's in a pharmacogenetically defined patient subset. Last year, Takeda began collaborating with Zinfandel, a company started by Roses, to conduct a study in which normal subjects between ages 68 and 83 will be randomized to receive either pioglitazone or placebo.
Previously conducted animal and clinical studies have shown that thiazolidinedione drugs, such as pioglitazone, improve cognition and dynamic functions of neuronal mitochondria in Alzheimer's disease in murine and human-derived neuronal cell culture models. Roses' team has studied pioglitazone's safety record for more than ten years while the drug has been used at higher doses in humans. Using their understanding of the drug's mechanism of action, the researchers have designed a Phase III trial in which participants will be given either placebo or a new formulation of low-dose pioglitazone only if they are deemed to be at high risk for developing Alzheimer's within five years.
Disease risk will be assessed with the help of a companion diagnostic that factors in the participant's age, APOE4 status, and TOMM40 status in order to predict the likelihood of developing mild cognitive impairment due to Alzheimer's. Those who fall in the low-risk category will be randomized to one of two placebo arms (PGx Reporter 01/12/2011).
Roses has published research showing that varying lengths of the TOMM40 rs10524523 poly-T polymorphism — located at intron 6 of the TOMM40 gene and linked to APOE ε3 and APOE ε4 polymorphisms — can be used to craft a three-allele risk prediction system for gauging the age of onset for Alzheimer's. Independently but simultaneously with the Phase III pioglitazone trial, researchers will also validate the genetic prognostic test for gauging which patients are at high risk for Alzheimer's-related mild cognitive impairment.
The rationale for using drugs for glucose control, such as pioglitazone, to treat people at heightened risk for getting Alzheimer's comes from early PET studies of the parts of the human brain associated with the disease, which showed that decreased glucose utilization may be a function of the APOE 4/4 genotype. In one study, published in 1996, Eric Reiman and research collaborators at Arizona's Aging and Disability Resource Center compared 11 normal people with the APOE 4/4 genotype against 22 people who were normal and had the 2/3 or the 3/3 genotype. They noted in that study a consistent decreased glucose utilization in multiple areas of the brain in normal people (of average age 50 years) with the APOE 4/4 genotype compared to those with no APOE 4 allele. Following this, researchers have consistently replicated decreased glucose utilization using PET studies in APOE4 carriers.
This decreased glucose utilization in genotypes associated with Alzheimer's "led us to start looking at [the diabetes treatment] rosiglitazone," Roses said. At the time, however, based on measurements of cerebral spinal fluid, researchers thought that thiazolidinedione diabetes treatments such as pioglitazone and rosiglitazone, sold by GlaxoSmithKline under the brand name Avandia, didn't get into the brain.
"What we now know is that [these drugs] get into the brain very rapidly and it gets cleared very rapidly, and we know this from the BOLD study,” Roses said. "The understanding that pioglitazone increases oxygen utilization in specific areas within the brain made it possible to use this technique in order to examine how that effect is accomplished, meaning do you have to go higher with the dose or do you have to go lower?"
With guidance from the BOLD data that a lower dose of pioglitazone had the best impact on brain functional connectivity, Takeda and Zinfandel are exploring different dosing and formulation strategies in humans. Although the Phase III study of pioglitazone in Alzheimer's patients was originally slated to start in October, that trial will begin after the researchers settle on the dose using human BOLD imaging studies.
The investigators are testing several low doses of the drug in humans to figure out the lowest dose that can be given to clinical trial participants over the five-year study period to minimize the risk of adverse reactions. Heart failure and bladder cancer are some of the serious ill effects that have been reported in diabetes patients receiving pioglitazone at higher doses and over prolonged periods.
Roses expects the Phase III study to begin by the end of this year or early next year.
Learning from Avandia's Failure
For some time now, researchers have theorized that Alzheimer's disease is a type of "diabetes of the brain." People whose brains have impaired ability to metabolize cerebral glucose often exhibit cognitive impairment and researchers feel this may be a warning sign of Alzheimer's.
Roses began following the effect of thiazolidinedione drugs on Alzheimer's disease while he was senior VP of genetics research and pharmacogenetics at GSK from 1997 to 2008. The company about a decade ago was testing out the "brain diabetes" Alzheimer's theory with Avandia, which was its best-selling diabetes drug before a study in 2007 linked the treatment with an increased risk of heart attacks.
Based on a Phase IIB pharmacogenetic-assisted trial that concluded in 2005, GSK researchers found that APOE4-negative Alzheimer's patients garnered a cognitive benefit from Avandia, but those studies did not pan out in the follow-up Phase III trial. In 2009, GSK reported that in a six-month study involving 553 patients with mild to moderate Alzheimer’s disease, normal diabetic doses of Avandia failed to improve cognition or behavior in people who were APOE4 non-carriers.
Since his departure from GSK, Roses' work exploring the relationship between age of Alzheimer's onset, TOMM40 lengths, and APOE4 status has yielded some clues as to what may have gone wrong in those earlier attempts.
The first Phase IIb trial at GSK to test rosiglitazone's effect in Alzheimer's disease patients by APOE carrier status didn't find a difference in the effect of the drug in APOE4 carriers. However, in non-carriers of APOE4, GSK researchers saw increased glucose utilization with 2 mg, 4 mg, and 8 mg doses of rosiglitazone. "This was very surprising," Roses recalled. "At the time, we thought the brain was going to be harder to get into and [in the literature] the drug was thought to be impermeable to the blood-brain barrier."
Then, again, in a Phase III study involving rosiglitazone in Alzheimer's patients there were signals that lower doses of the drug might have a greater impact than higher doses. When patients were given either 2 mg or 8 mg of the drug, the p-value for those who received the 2 mg dose was 0.07, very close to reaching statistical significance, while the p-value for the 8 mg dose wasn't even close to being significant.
However, it is worth noting that in those trials, a large portion of the Phase III study cohort was from Asian countries, predominantly China, a population that carries APOE4 at much lower frequencies than Caucasians. The Phase IIb study, comparatively, was done in all Caucasians.
"So, if you were recruiting patients with mild to moderate Alzheimer's disease correctly, you'd expect to have a lower frequency of APOE4s in the Chinese population. In fact, in those [Phase III] study populations there was an increase in the proportion of APOE4," Roses said.
It has been suggested that some investigators in the trial were recruiting Alzheimer's patients by APOE4 carrier status, resulting in a much higher proportion of APOE4-positive patients than is seen in the general population. If that was true, then researchers "averaged out the possibility of seeing an effect [of rosiglitazone] in the APOE4-negatives," Roses noted. "Still, the hint was there that the low dose of rosiglitazone might have had an effect." This finding was published three years after Roses left GSK in 2010 in Dementia and Geriatric Cognitive Disorders.
Only after the subsequent discovery of TOMM40 in 2009 and its genetic relationship to Alzheimer’s disease age of onset distributions could these data be re-modeled. Roses requested the DNA samples for the trial from GSK two years ago, but the company did not make the samples available for retesting for TOMM40 polymorphisms.
Seeking the Lowest Dose
Still, going off the early signals from the Avandia studies, Roses and his team crafted the rationale for the BOLD rat trial. The data suggest that pioglitazone at doses much lower than those tested in the rosiglitazone trials may improve brain functional connectivity in people at heightened risk of getting mild cognitive impairment from Alzheimer's.
Takeda and Zinfandel have not yet announced which pioglitazone doses they will use in the Phase III trial, but the companies are in the process of conducting another study, called the Confirmatory BOLD trial, to test even lower doses of the drug in humans.
In the rosiglitazone study published in Dementia and Geriatric Cognitive Disorders, researchers found that Alzheimer's patients experienced fewer toxicities with the 2 mg dose. So, when it comes to looking at pioglitazone's impact on mild cognitive impairment due to Alzheimer's, Roses and his team are interested in seeing how low they can go in dosing the drug.
"When you do a drug study, you're usually trying to insure efficacy so you can get it through the FDA, so you push the drug to almost toxicity in order to get the clinical effect. But in terms of what's the lowest dose you can get for the drug, once it's on the market, no one's going to be studying the drug in that setting," Roses said. "But if you go lower, you usually can get rid of a lot of side effects."
As diabetes treatments, the labels for both pioglitazone and rosiglitazone include a class warning noting that thiazolidinediones "cause or exacerbate" congestive heart failure. Due to the US Food and Drug Administration's growing concerns over this adverse drug reaction, the agency restricted the sale of Avandia last year to only those patients who don’t respond well to Actos.
Meanwhile, based on an interim analysis of a study that found that patients taking Actos for longer than one year may have an increased risk of bladder cancer, the FDA last year updated the drug's label to warn patients that there "may be" a treatment-related increased risk for the disease. France and Germany have asked doctors to stop prescribing the drug to diabetes patients.
Patients at heightened risk for Alzheimer's disease may be willing to accept a different risk/benefit profile from these drugs than diabetes patients since there is a critical need for a safe drug to treat or delay Alzheimer’s. Still, if the risk of adverse reactions are confirmed after completed analysis, it could make it difficult for Takeda to promote pioglitazone as a delay-of-onset treatment for Alzheimer's.
Recognizing this, Roses and his team are trying to find the lowest possible dose that will enable Takeda to study the drug in the Phase III trial in patients with an acceptable safety profile without compromising its efficacy. There was additional experience at GSK with a 2 mg dose of rosigtitazone in other indications, and in those studies the rate of treatement-related side-effects were markedly diminished.
"In some ways, the situation [with thiazolidinediones] is reminiscent of what happened with birth control pills," Roses said. When those drugs first came on the market more than 50 years ago, the doses were high and people experienced a host of adverse reactions, including cardiac and blood pressure problems. Over the years, however, new birth control pills have required markedly lower doses.
"The expectation would be that the dose, at such a minimal level, will be effective in delaying the onset of mild cognitive impairment while alleviating many of the side effects" seen with thiazolidinediones, Roses added. "We will know that when we have seen the data."
Labels: actos, cardiac-and-blood-pressure-problems, FDA, roses
// posted by neurofuture9:49 AM permanent link
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7.21.2012
Nicotine Patches May Slow Cognitive Decline in Alzheimer's Patients
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A patch containing nicotine may be helpful in slowing or even arresting mild cognitive decline in Alzheimer's patients. The fact that nicotine enhances cognition is – unfortunately – not news to smokers. In fact, that's one reason they keep lighting up in the face of dire health risks. However, the researchers who developed the new medication appear to have been able to tease apart the cognitive benefit from nicotine's addictive properties.
The scientists presented their findings at Alzheimer's Association International Conference in Vancouver. Of 74 subjects enrolled, 39 received the nicotine drug and 35 got a placebo. "This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with mild cognitive impairment over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing," the authors wrote.
"We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with mild cognitive impairment." However, the team cautioned that larger studies are necessary to determine whether or not these effects are clinically important.
The scientists presented their findings at Alzheimer's Association International Conference in Vancouver. Of 74 subjects enrolled, 39 received the nicotine drug and 35 got a placebo. "This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with mild cognitive impairment over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing," the authors wrote.
"We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with mild cognitive impairment." However, the team cautioned that larger studies are necessary to determine whether or not these effects are clinically important.
Labels: alzheimers-association-international-conference, cognitive-impairment
// posted by neurofuture11:46 AM permanent link
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7.20.2012
Scientists 'Read' Monkeys Inner Thoughts
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Anyone who has looked at the jagged recording of the electrical activity of a single neuron in the brain must have wondered how any useful information could be extracted from such a frazzled signal.
But over the past 30 years, researchers have discovered that clear information can be obtained by decoding the activity of large populations of neurons.
Now, scientists at Washington University in St. Louis, who were decoding brain activity while monkeys reached around an obstacle to touch a target, have come up with two remarkable results.
Their first result was one they had designed their experiment to achieve: they demonstrated that multiple parameters can be embedded in the firing rate of a single neuron and that certain types of parameters are encoded only if they are needed to solve the task at hand.
Their second result, however, was a complete surprise. They discovered that the population vectors could reveal different planning strategies, allowing the scientists, in effect, to read the monkeys' minds.
By chance, the two monkeys chosen for the study had completely different cognitive styles. One, the scientists said, was a hyperactive type, who kept jumping the gun, and the other was a smooth operator, who waited for the entire setup to be revealed before planning his next move. The difference is clearly visible in their decoded brain activity.
The study was published in the July 19th advance online edition of the journal Science.
Read More at Eureka Alert
Labels: daniel-moran, Eureka-alert, science, washington-university-of-St.-Louis
// posted by neurofuture11:34 AM permanent link
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7.19.2012
Slow Gait Tied to Higher Risk of Cognitive Decline
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Problems walking including slow gait and a short stride are associated with an increased risk of cognitive decline, Mayo Clinic researchers have discovered. Their findings are being presented at the Alzheimer's Association International Conference July 14–19 in Vancouver, British Columbia. Mayo Clinic researchers are presenting on several topics, including the following:
Gait disturbances linked with decline in cognitive function
Researchers measured the stride length, cadence and velocity of more than 1,341 participants through a computerized gait instrument at two or more visits roughly 15 months apart. Researchers found that study participants with lower cadence, velocity and length of stride experienced significantly larger declines in global cognition, memory and executive function.
"These results support a possible role of gait changes as an early predictor of cognitive impairment," said study author Rodolfo Savica, M.D., a Mayo Clinic neurologist.
Labels: 1341-participants-in-study, alzheimers-association-international-conference, rodolfo-savica
// posted by neurofuture11:21 AM permanent link
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7.18.2012
Alcohol Harms Thinking In Older Adults, Confirm Researchers
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Certain types of alcohol use after age 65 may affect memory and thinking, according to two studies that raise new questions about earlier research that suggested drinking may stymie cognitive decline.
People 65 and older who regularly consumed four or more alcoholic beverages at a time, a situation described in the study as binge-drinking, were more likely to have the highest drop-off in brain function and the most memory decline, according to one result. A second study reported that women who indulged heavily early in life or were moderate drinkers after 65 were more likely to have cognitive impairment.
Drinking alcohol had been thought to reduce the risk of cognitive decline in some older people, the Alzheimer’s Association said in a statement. Today’s reports, presented at the Alzheimer’s Association International Conference in Vancouver, suggest more research is needed.
“It’s clear that the pattern of drinking is important, that increasing alcohol consumption even to moderate levels may not be a good idea, and that there is a lot we don’t know about this topic,” said Iain Lang, lead author of the binge-drinking study and a senior lecturer in public health at the University of Exeter’s Peninsula College of Medicine and Dentistry in the U.K. “Older adults should be cautious.”
New research should be done to look at the effects of alcohol consumption, including how binge drinking at younger ages may affect people later in life, Lang wrote in an e-mail.
Alzheimer’s Victims
About 5.4 million Americans have Alzheimer’s, the most common type of dementia, and by 2050 that number is expected to grow to as many as 16 million, according to the Alzheimer’s Association. The number of people worldwide with the condition is expected to swell to 115 million by 2050.
Lang and other researchers analyzed data from 5,075 people ages 65 and older who were part of the U.S. Health and Retirement Study. Data was collected in 2002 and participants were followed for eight years.
In the study, 167 men and 47 women reported binge drinking once a month and 86 men and 15 women said they engaged in binge drinking on average twice a month.
The research found that those who reported binge drinking once a month were 62 percent more likely than those who didn’t to be in the group with the greatest decline in cognitive function and 27 percent more likely to be in the group with the greatest memory drop-off. For those who engaged in the heavy drinking twice a month, they were 147 percent more likely to be in the group with the greatest cognitive decline and 149 percent more likely to be in the group with the greatest memory loss, the study showed.
Binge Drinking
Today’s study is the first to look at binge drinking in older adults, Lang said.
“Binge drinking, in particular, may pose risks to health later in life that have not previously been identified,” he said. “Physicians or others who advise patients about their levels of alcohol consumption should be aware that it’s not only how much people drink but how they drink that may be important in relation to health.”
In the other study, researchers looked at 1,306 women at least 65 years old who were followed for 20 years. At the start of the study, 41 percent didn’t drink, 50 percent were considered light drinkers having zero to seven drinks per week and 9 percent were considered moderate drinkers, having seven to 14 drinks a week.
Drinking Habits
They found that those who drank more when they were younger then at the start of the study were at a 30 percent increased risk of developing cognitive impairment, while women who started drinking during the trial had a 200 percent increased risk of cognitive impairment. The study also showed that women who consumed seven to 14 drinks a week toward the end of the study were about 60 percent more likely to develop cognitive impairment.
“These findings suggest that alcohol use in late-life may not be beneficial for cognitive function in older women,” said Tina Hoang, the lead study author and clinical research coordinator at the San Francisco Veterans Administration Medical Center, in a statement. “It may be that the brains of oldest old adults are more vulnerable to the effects of alcohol, but it is also possible that factors associated with changing alcohol use related to coping or loss could be involved. Clinicians should carefully assess their older patients for both how much they drink and any changes in patterns of alcohol use.”
Labels: Iain-Lang, SF-Veterans-Hospital, university-of-Exeter
// posted by neurofuture11:53 AM permanent link
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7.13.2012
Alzheimer's Plaques in PET Brain Scans Identify Future Cognitive Decline
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Among patients with mild or no cognitive impairment, brain scans using a new radioactive dye can detect early evidence of Alzheimer's disease that may predict future decline, according to a multi-center study led by researchers at Duke University Medical Center.
The finding is published online July 11, 2012, in the journal Neurology, the medical journal of the American Academy of Neurology. It expands on smaller studies demonstrating that early detection of tell-tale plaques could be a predictive tool to help guide care and treatment decisions for patients with Alzheimer's disease.
"Even at a short follow-up of 18 months we can see how the presence of amyloid plaques affects cognitive function," said P. Murali Doraiswamy, M.D., professor of psychiatry at Duke who co-led the study with R. Edward Coleman, M.D., professor of radiology at Duke . "Most people who come to the doctor with mild impairment really want to know the short-term prognosis and potential long-term effect."
Doraiswamy said such knowledge also has some pitfalls. There is no cure for Alzheimer's disease, which afflicts 5.4 million people in the United States and is the sixth-leading cause of death among U.S. adults. But he said numerous drugs are being investigated, and identifying earlier disease would improve research into their potential benefits and speed new discoveries, while also enhancing care and treatment of current patients.
In the Neurology study, 151 people who had enrolled in a multi-center test of a new radioactive dye called florbetapir (Amyvid) were recruited to participate in a 36-month analysis. Of those participants, 69 had normal cognitive function at the start of the study, 51 had been diagnosed with mild impairment, and 31 had Alzheimer's dementia.
All completed cognitive tests and underwent a brain scan using Positron Emission Tomography, or PET imaging. The technology uses radioactive tracers designed to highlight specific tissue to create a three-dimensional picture of an organ or a biological function.
The dye used in the study, florbetapir, was recently approved by the U.S. Food and Drug Administration for PET imaging of the brain to estimate beta-amyloid plaque density in patients who are being evaluated for cognitive impairment. It binds to the amyloid plaques that characterize Alzheimer's disease, providing a window into the brain to see if the plaques have formed, and how extensively.
Patients in the study were reassessed with additional cognitive exams at 18 months and 36 months. At the 18-month point, patients with mild cognitive impairment who had PET evidence of plaque at the trial's start worsened to a great degree on cognitive tests than patients who had no evidence of plaque at the trial's start. Twenty-nine percent of the plaque-positive patients in this group developed Alzheimer's dementia, compared to 10 percent who started with no plaque.
Cognitively normal patients with a plaque-positive PET scan at the start of the study also showed more mental decline at 18 months compared to those who were negative for plaque.
The study additionally found that people with negative scans reversed from minimally impaired to normal more often than people with positive PET scan, suggesting test anxiety or concentration problems could have affected their initial performance.
"For the most part we have been blind about who would progress and who wouldn't, so this approach is a step toward having a biomarker that predicts risk of decline in people who are experiencing cognitive impairment," Doraiswamy said.
He said the study's results provide initial data that needs to be verified by additional research. Final, 36-month data from the study has been completed and will be presented at the Alzheimer's Association International Conference this week in Vancouver, Canada. Doraiswamy also cautioned that florbetapir is currently not approved to predict the development of dementia or other neurologic conditions and stressed that it should not be used as a screening tool in otherwise normal or minimally impaired people. Likewise, a positive scan is not necessarily diagnostic for Alzheimer's by itself.
In addition to Doraiswamy and Coleman (who died in June), study authors included; Reisa A. Sperling and Keith A. Johnson of Massachusetts General Hospital, Boston Medical School; Eric M. Reiman of Banner Alzheimer's Institute; Mat D. Davis of the University of Pennsylvania; Michael Grundman of Global R&D Partners and the University of California, San Diego; Marwan N. Sabbagh of Banner-Sun Health Research Institute; Carl H. Sadowsky of Nova SE University; Adam S. Fleisher of Banner Alzheimer's Institute and UCSD; and Alan Carpenter, Christopher M. Clark (deceased), Abhinay D. Joshi, Mark A. Mintun, Daniel M. Skovronsky, and Michael J. Pontecorvo of Avid Radiopharmaceuticals.
The study was funded by Eli Lilly/Avid Radiopharmaceuticals, which markets florbetapir and conducted by Avid and the AV45-A11 study group, a consortium of Alzheimer's clinical research centers. Doraiswamy receives advisory and speaker fees from Lilly/Avid, as well as other companies, and owns shares in Sonexa and Clarimedix.
Labels: coleman, doraiswamy, florbetapir, PET-SCAN
// posted by neurofuture3:24 PM permanent link
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7.02.2012
Rapamycin Enhances Learning and Memory in Young Mice
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Cognitive skills such as learning and memory diminish with age in everyone, and the drop-off is steepest in Alzheimer's disease. Texas scientists seeking a way to prevent this decline reported exciting results this week with a drug that has Polynesian roots.
The researchers, appointed in the School of Medicine at The University of Texas Health Science Center San Antonio, added rapamycin to the diet of healthy mice throughout the rodents' life span. Rapamycin, a bacterial product first isolated from soil on Easter Island, enhanced learning and memory in young mice and improved these faculties in old mice, the study showed.
"We made the young ones learn, and remember what they learned, better than what is normal," said Veronica Galvan, Ph.D., assistant professor of physiology at the Barshop Institute for Longevity and Aging Studies, part of the UT Health Science Center. "Among the older mice, the ones fed with a diet including rapamycin actually showed an improvement, negating the normal decline that you see in these functions with age."
The drug also lowered anxiety and depressive-like behavior in the mice, Dr. Galvan said. Anxiety and depression are factors that impair human cognitive performance. Lead author Jonathan Halloran conducted scientifically reliable tests to accurately measure these cognitive components in the rodents.
Venturing into the open
Mice are burrowers that prefer tunnels with walls. To observe behavior, Halloran used an elevated maze of tunnels that led to a catwalk. "All of a sudden the mice are in open space," Halloran said. "It's pretty far from the floor for their size, sort of like if a person is hiking and suddenly the trail gets steep. It's pretty far down and not so comfortable."
Mice with less anxiety were more curious to explore the catwalk. "We observed that the mice fed with a diet containing rapamycin spent significantly more time out in the open arms of the catwalk than the animals fed with a regular diet," Halloran said.
The second test measured depressive-like behavior in the rodents. Mice do not like to be held by their tails, which is the way they are moved from cage to cage. Inevitably they struggle to find a way out. "So we can measure how much and how often they struggle as a measure of the motivation they have to get out of an uncomfortable situation," Dr. Galvan said.
Rapamycin acts like an antidepressant
Some mice barely struggle to get free, but if an antidepressant is administered they struggle a lot more. This behavior is very sensitive to the action of antidepressants and is a reliable measure of whether a drug is acting like an antidepressant, Dr. Galvan said.
Labels: barshop-institue, galvan, rapamycin, u-t-health-sciences-center
// posted by neurofuture11:56 AM permanent link
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