Alzheimer's Plaques in PET Brain Scans Identify Future Cognitive Decline

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.

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New Biomarker In The Blood May Help Predict Alzheimer's Disease

ScienceDaily (July 18, 2012) — Higher levels of a certain fat in the blood called ceramides may increase a person's risk of developing Alzheimer's disease, according to a study published in the July 18, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.

"Our study identifies this biomarker as a potential new target for treating or preventing Alzheimer's disease," said study author Michelle M. Mielke, PhD, an epidemiologist with the Mayo Clinic in Rochester, Minn. Mielke was with Johns Hopkins University at the time of the research.


For the study, 99 women between the ages of 70 and 79 and free of dementia in the Women's Health and Aging Study II had their blood tested for levels of serum ceramides, a fatty compound found throughout the body that is associated with inflammation and cell death. The participants were placed into three groups: high, middle and low levels of ceramides. They were then followed for up to nine years. Of the 99 participants, 27 developed dementia and 18 of those were diagnosed with probable Alzheimer's disease.


The study found that women who had the highest levels of the biomarker were 10 times more likely to develop Alzheimer's disease than women with the lowest levels. Those with middle levels of the biomarker were nearly eight times more likely to develop the disease than those with the lowest levels.
"These findings are important because identifying an accurate biomarker for early Alzheimer's that requires little cost and inconvenience to a patient could help change our focus from treating the disease to preventing or delaying it," said Valory Pavlik, PhD, with the Alzheimer's Disease and Memory Disorders Center of Baylor College of Medicine in Houston and a member of the American Academy of Neurology, in an accompanying editorial.


According to Pavlik, "While a larger, more diverse study is needed to confirm these findings, projections that the global prevalence of Alzheimer's disease will double every 20 years for the foreseeable future have certainly increased the sense of urgency among researchers and health care agencies to identify more effective screening, prevention and treatment strategies."
The study was supported by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke and the Johns Hopkins Older Americans Independence Center.

Adaptable Decision Making In The Brain 

ScienceDaily (June 19, 2012) — Researchers at the University of Iowa, together with colleagues from the California Institute of Technology and New York University, have discovered how a part of the brain helps predict future events from past experiences. The work sheds light on the function of the front-most part of the frontal lobe, known as the frontopolar cortex, an area of the cortex uniquely well developed in humans in comparison with apes and other primates.

Making the best possible decisions in a changing and unpredictable environment is an enormous challenge. Not only does it require learning from past experience, but it also demands anticipating what might happen under previously unencountered circumstances. Past research from the UI Department of Neurology was among the first to show that damage to certain parts of the frontal lobe can cause severe deficits in decision making in rapidly changing environments. The new study from the same department on a rare group of patients with damage to the very frontal part of their brains reveals a critical aspect of how this area contributes to decision making. The findings were published June 19 in the Journal of Neuroscience.

"We gave the patients four slot machines from which to pick in order to win money. Unbeknownst to the patients, the probability of getting money from a particular slot machine gradually and unpredictably changed during the experiment. Finding the strategy that pays the most in the long run is a surprisingly difficult problem to solve, and one we hypothesized would require the frontopolar cortex," explains Christopher Kovach, Ph.D., a UI post-doctoral fellow in neurosurgery and first author of the study.

Contrary to the authors' initial expectation, the patients actually did quite well on the task, winning as much money, on average, as healthy control participants.

"But when we compared their behavior to that of subjects with intact frontal lobe, we found they used a different set of assumptions about how the payoffs changed over time," Kovach says. "Both groups based their decisions on how much they had recently won from each slot machine, but healthy comparison subjects pursued a more elaborate strategy, which involved predicting the direction that payoffs were moving based on recent trends. This points towards a specific role for the frontopolar cortex in extrapolating recent trends."



Kovach's colleague and study author Ralph Adolphs, Ph.D., professor of neuroscience and psychology at the California Institute of Technology, adds that the study results "argue that the frontopolar cortex helps us to make short-term predictions about what will happen next, a strategy particularly useful in environments that change rapidly -- such as the stock market or most social settings."



Adolphs also hold an adjunct appointment in the UI Department of Neurology.



The study's innovative approach to understanding the function of this part of the brain uses model-based analyses of behavior of patients with specific and precisely characterized areas of brain damage. These patients are members of the UI's world-renowned Iowa Neurological Patient Registry, which was established in 1982 and has more than 500 active members with selective forms of damage, or lesions, to one or two defined regions in the brain.



"The University of Iowa is one of the few places in the world where you could carry out this kind of study, since it requires carefully assessed patients with damage to specific parts of their brain," says study author Daniel Tranel, Ph.D., UI professor of neurology and psychology and director of the UI Division of Behavioral Neurology and Cognitive Neuroscience.



In a final twist to the finding, the strategy taken by lesion patients was actually slightly better than the one used by comparison subjects. It happened that the task was designed so that the trends in the payoffs were, in fact, random and uninformative.


"The healthy comparison subjects seemed to perceive trends in what was just random noise," Kovach says.



This implies that the functions of the frontopolar cortex, which support more complex and detailed models of the environment, at times come with a downside: setting up mistaken assumptions.



"To the best of my knowledge this is the first study which links a normal tendency to see a nonexistent pattern in random noise, a type of cognitive bias, to a particular brain region," Kovach notes.



The researchers next want to investigate other parts of the frontal cortex in the brain, and have also begun to record activity directly from the brains of neurosurgical patients to see how single cells respond while making decisions. The work is also important to understand difficulties in decision making seen in disorders such as addiction.



The study, "Anterior prefrontal cortex contributes to action selection through tracking of recent reward trends," also included authors David Rudrauf from the University of Iowa, John O'Doherty from the California Institute of Technology, and Nathaniel Daw from New York University.

Breaking Point: When Does Head Trauma in Sports Lead to Memory Loss?

ScienceDaily (Apr. 18, 2012) — A new study suggests there may be a starting point at which blows to the head or other head trauma suffered in combat sports start to affect memory and thinking abilities and can lead to chronic traumatic encephalopathy, or CTE, in the brain.



The research was released April 18 and will be presented as part of the Emerging Science program at the American Academy of Neurology's 64th Annual Meeting in New Orleans April 21 to April 28, 2012.

"While we already know that boxing and other combat sports are linked to brain damage, little is known about how this process develops and who may be on the path to developing CTE, which is a degenerative brain disease found in athletes and others with a history of multiple concussions and brain damage," said study author Charles Bernick, MD, of the Cleveland Clinic in Cleveland and a member of the American Academy of Neurology. CTE is only diagnosed through autopsy after death, but symptoms include memory loss, aggression and difficulty thinking.

The study involved 35 boxers and 43 mixed martial arts athletes with an average age of 29 who were part of the ongoing Professional Fighters Brain Health Study. The fighters were given computer tests that measured memory and thinking skills and underwent MRI brain scans. Years of fighting and number of fights were recorded based on self-reporting and published records. The fighters were then split into two groups: those who fought for nine or fewer years and those with more than nine years of fighting history.

In both groups, those with more years of fighting and more fights per year were more likely to have lower brain volumes in three areas of the brain. In those with fewer than nine years of fighting, there was no relationship between the years of fighting or the number of fights per year and the results on memory and thinking tests. But for those who had fought for nine or more years, those with more fights per year performed worse on the thinking and memory tests than those with fewer fights per year.

"Our study shows there appears to be a threshold at which continued repetitive blows to the brain begin to cause measurable changes in memory and thinking, despite brain volume changes that can be found earlier," said Bernick.

The study was supported by the Lincy Foundation.