Neuropsychological assessment more efficient than MRI for tracking disease progression in memory clinic patients

Progression of disease in memory clinic patients can be tracked efficiently with 45 minutes of neuropsychological testing, new research shows. MRI measures of brain atrophy were shown to be less reliable to pick up changes in the same patients. This finding has important implications for the design of clinical trials of new anti-Alzheimer drugs. If neuropsychological assessment is used as the outcome measure or “gold standard,” fewer patients would be needed to conduct such trials, or the trials may be of shorter duration. Investigators at the University of Amsterdam, The Netherlands, have shown that progression of disease in memory clinic patients can be tracked efficiently with 45 minutes of neuropsychological testing. MRI measures of brain atrophy were shown to be less reliable to pick up changes in the same patients. This finding has important implications for the design of clinical trials of new anti-Alzheimer drugs. If neuropsychological assessment is used as the outcome measure or “gold standard,” fewer patients would be needed to conduct such trials, or the trials may be of shorter duration. The US Food and Drug Administration and its counterparts in other countries, such as the European Medicines Agency, require that pharmaceutical companies test and prove the effectiveness of new drugs through experimental studies. In the case of Alzheimer’s disease, this means amelioration of cognitive and behavioral symptoms or at least slowing down the rate of cognitive and behavioral decline. Until now the outcome measures in this type of research have been cognitive and behavioral rating scales, such as the Alzheimer Disease Assessment Scale (ADAS). If the effect of a new drug cannot be demonstrated with such a scale, the drug will not be approved. The problem with scales like the ADAS is that they are quite crude and cannot pick up subtle changes, especially in early stages of the disease. As an alternative, MRI measures of brain atrophy have been proposed as outcome in clinical trials, because of allegedly better properties to detect subtle changes. This implies that fewer patients are needed in clinical trials of new drugs to show a treatment effect. The Dutch investigators tested this claim at the memory clinic of the Academic Medical Centre, University of Amsterdam, by comparing neuropsychological assessment and MRI measures of brain atrophy in 62 patients with no or early cognitive impairment, but no dementia. At baseline and after two years, neurologists examined the study participants and judged whether or not their cognition was normal. After two years of follow-up, twenty-eight patients were considered to be normal, and 34 had mild cognitive impairment or had progressed to dementia, mostly Alzheimer’s disease. At baseline and at follow-up all patients had a state-of-the-art MRI scan, and memory and other cognitive functions were tested with five standard neuropsychological tests. In the group that the neurologists considered normal at follow-up, cognitive performance was indeed normal at baseline, and it remained so after two years. In the group that was considered impaired, however, cognition was already abnormal at baseline and it declined considerably over the next two years. The MRI measures concerned volumes of the left and right hippocampus, which are extremely important for memory functioning, and are the first to degenerate during the Alzheimer disease process. The volume of the hippocampus decreased less than 1% in the normal group during the follow-up interval, and more than 3% in the impaired group. The pattern of findings was similar for both techniques, but MRI showed less pronounced differences between both groups at baseline than the cognitive tests, and more importantly, less pronounced differences in rate of change. Using figures on rates of change as collected in this study, one may calculate the numbers of patients that would be needed for a hypothetical clinical trial of a new drug. The investigators concluded that only half as many patients would be needed if neuropsychological assessment were used as the gold standard rather than MRI measures of brain atrophy. However, Dr, Edo Richard, one of the neurologists conducting the study, says, “Whichever outcome is selected, evaluation of functioning as it can be noticed by patients will always be needed to confirm the clinical relevance of any treatment effect.” Journal Reference: 1.Ben Schmand, Anne Rienstra, Hyke Tamminga, Edo Richard, Willem A. van Gool, Matthan W.A. Caan, Charles B. Majoie. Responsiveness of Magnetic Resonance Imaging and Neuropsychological Assessment in Memory Clinic Patients. Journal of Alzheimer’s Disease, January 2014 DOI: 10.3233/JAD-131484

Chronic pain research delves into brain: New insight into how brain responds to pain

Source:University of Adelaide Summary:New insights into how the human brain responds to chronic pain could eventually lead to improved treatments for patients, researchers say. Chronic pain is common throughout the world. More than 100 million Americans are believed to be affected by chronic pain. "People living with chronic headache and other forms of chronic pain may experience reduced quality of life, as the pain often prevents them from working, amongst other things. It is therefore imperative that we understand the causes of chronic pain, not just attempt to treat the symptoms with medication," the lead author said.Share This Neuroplasticity is the term used to describe the brain's ability to change structurally and functionally with experience and use. "Neuroplasticity underlies our learning and memory, making it vital during early childhood development and important for continuous learning throughout life," says Dr Ann-Maree Vallence, a Postdoctoral Fellow in the University of Adelaide's Robinson Institute. "The mechanisms responsible for the development of chronic pain are poorly understood. While most research focuses on changes in the spinal cord, this research investigates the role of brain plasticity in the development of chronic pain." Chronic pain is common throughout the world. In Australia, approximately 20% of adults suffer moderate to severe chronic pain. More than 100 million Americans are believed to be affected by chronic pain. Dr Vallence, who is based in the Robinson Institute's Neuromotor Plasticity and Development Group, has conducted a study on patients with chronic tension-type headache (CTTH), a common chronic pain disorder. CTTH is characterized by a dull, constant feeling of pressure or tightening that usually affects both sides of the head, occurring for 15 days or more per month. Other symptoms include poor sleep, irritability, disturbed memory and concentration, and depression and anxiety. "People living with chronic headache and other forms of chronic pain may experience reduced quality of life, as the pain often prevents them from working, amongst other things. It is therefore imperative that we understand the causes of chronic pain, not just attempt to treat the symptoms with medication," Dr Vallence says. In this study, participants undertook a motor training task consisting of moving their thumb as quickly as possible in a specific direction. The change in performance (or learning) on the task was tracked by recording how quickly subjects moved their thumb. A non-invasive brain stimulation technique was also used to obtain a measure of the participants' neuroplasticity. "Typically, when individuals undertake a motor training task such as this, their performance improves over time and this is linked with a neuroplastic change in the brain," Dr Vallence says. "The people with no history of chronic pain got better at the task with training, and we observed an associated neuroplastic change in their brains. However, our chronic headache patients did not get better at the task and there were no associated changes in the brain, suggesting impaired neuroplasticity. "These results provide a novel and important insight into the cause of chronic pain, and could eventually help in the development of a more targeted treatment for CTTH and other chronic pain conditions," she says

Play it again, Sam: How the brain recognizes familiar music

Source:McGill University Summary:Research reveals that the brain’s motor network helps people remember and recognize music that they have performed in the past better than music they have only heard. A recent study sheds new light on how humans perceive and produce sounds, and may pave the way for investigations into whether motor learning could improve or protect memory or cognitive impairment in aging populations.Share This For the study, researchers recruited twenty skilled pianists from Lyon, France. The group was asked to learn simple melodies by either hearing them several times or performing them several times on a piano. Pianists then heard all of the melodies they had learned, some of which contained wrong notes, while their brain electric signals were measured using electroencephalography (EEG). Credit: Palmer, Mathias McGill University[Click to enlarge image] For the study, researchers recruited twenty skilled pianists from Lyon, France. The group was asked to learn simple melodies by either hearing them several times or performing them several times on a piano. Pianists then heard all of the melodies they had learned, some of which contained wrong notes, while their brain electric signals were measured using electroencephalography (EEG).Credit: Palmer, Mathias McGill University Research from McGill University reveals that the brain's motor network helps people remember and recognize music that they have performed in the past better than music they have only heard. A recent study by Prof. Caroline Palmer of the Department of Psychology sheds new light on how humans perceive and produce sounds, and may pave the way for investigations into whether motor learning could improve or protect memory or cognitive impairment in aging populations. The research is published in the journal Cerebral Cortex. "The memory benefit that comes from performing a melody rather than just listening to it, or saying a word out loud rather than just hearing or reading it, is known as the 'production effect' on memory," says Prof. Palmer, a Canada Research Chair in Cognitive Neuroscience of Performance. "Scientists have debated whether the production effect is due to motor memories, such as knowing the feel of a particular sequence of finger movements on piano keys, or simply due to strengthened auditory memories, such as knowing how the melody tones should sound. Our paper provides new evidence that motor memories play a role in improving listeners' recognition of tones they have previously performed." For the study, researchers recruited twenty skilled pianists from Lyon, France. The group was asked to learn simple melodies by either hearing them several times or performing them several times on a piano. Pianists then heard all of the melodies they had learned, some of which contained wrong notes, while their brain electric signals were measured using electroencephalography (EEG). "We found that pianists were better at recognizing pitch changes in melodies they had performed earlier," said the study's first author, Brian Mathias, a McGill PhD student who conducted the work at the Lyon Neuroscience Research Centre in France with additional collaborators Drs. Barbara Tillmann and Fabien Perrin. The team found that EEG measurements revealed larger changes in brain waves and increased motor activity for previously performed melodies than for heard melodies about 200 milliseconds after the wrong notes. This reveals that the brain quickly compares incoming auditory information with motor information stored in memory, allowing us to recognize whether a sound is familiar. "This paper helps us understand 'experiential learning', or 'learning by doing', and offers pedagogical and clinical implications," said Mathias, "The role of the motor system in recognizing music, and perhaps also speech, could inform education theory by providing strategies for memory enhancement for students and teachers." This study was conducted within the framework of the European Erasmus Mundus Auditory Cognitive Neuroscience exchange program, in which North American researchers complete a research project in collaboration with a European laboratory for 6-12 months.

The Brain Processes Complex Stimuli More Cumulatively Than We Thought

The finding represents a new view of how the brain creates internal representations of the visual world. "We are excited to see if this novel view will dominate the wider consensus" said senior author Dr. Miyashita, who is also Professor of Physiology at the University of Tokyo's School of Medicine, "and also about the potential impact of our new computational principle on a wide range of views on human cognitive abilities." The brain recalls the patterns and objects we observe by developing distinct neuronal representations that go along with them (this is the same way it recalls memories). Scientists have long hypothesized that these neuronal representations emerge in a hierarchical process limited to the same cortical region in which the representations are first processed. Because the brain perceives and recognizes the external world through these internal images, any new information about the process by which this takes place has the power to inform our understanding of related functions, including knowledge acquisition and memory. However, studies attempting to uncover the functional hierarchy involved in the cortical process of visual stimuli have tried to characterize this hierarchy by analyzing the activity of single nerve cells, which are not necessarily correlated with neurons nearby, thus leaving these analyses lacking. In a new study appearing in the 12 July issue of the journal Science, lead author Toshiyuki Hirabayashi and colleagues focus not on single neurons but instead on the relationship between neuron pairs, testing the possibility that the representation of an object in a single brain region emerges in a hierarchically lower brain area. "I became interested in this work," said Dr. Hirabayashi, "because I was impressed by the elaborate neuronal circuitry in the early visual system, which is well-studied, and I wanted to explore the circuitry underlying higher-order visual processing, which is not yet fully understood." Hirabayashi and colleagues analyzed nerve cell pairs in cortical areas TE and 36, the latter of which is hierarchically higher, in two adult macaques. After these animals looked at six sets of paired stimuli for several months to learn to associate related objects (a process that can lead to pair-coding neurons in the brain), the researchers recorded neuron responses in areas TE and 36 of both animals as they again performed this task. The neurons exhibited pair association, but not where the researchers would have thought. "The most surprising result," said senior author Dr. Yasushi Miyashita "was that the neuronal circuit that generated pair-association was found only in area TE, not in area 36." Indeed, based on previous studies, which indicated that the number of pair-coding neurons in area TE is much smaller, the researchers would have expected the opposite. During their study, Miyashita and other team members observed that in region TE of the macaque cortex, unit 1 neurons (or source neurons) provided input to unit 2 neurons (or target neurons), which -- unlike unit 1 neurons -- responded to both members of a stimulus pair. "The representations generated in area TE did not reflect a mere random fluctuation of response patterns," explained Dr. Miyashita, "but rather, they emerged as a result of circuit processing inherent to that area of the brain." In area 36, meanwhile, members of neuron pairs behaved differently; on average, unit 1 as well as unit 2 neurons responded to both members of a stimulus pair. Neurons in area 36 received input from area TE, but only from its unit 2 neurons. Taken together, these findings lead the authors to hypothesize the existence of a hierarchical relationship between regions TE and 36, in which paired associations first established in the former region are propagated to the latter one. Here, area 36 represents the next level of a so-called feed forward hierarchy. The work by Hirabayashi and colleagues suggests that the detailed representations of objects commonly observed in the brain are attained not by buildup of representations in a single area, but by emergence of these representations in a hierarchically prior area and their subsequent transfer to the brain region that follows. There, they become sufficiently prevalent for the brain to register. The work also reveals that the brain activity involved in recreating visual stimuli emerges in a hierarchically lower brain area than previously thought. Moving forward, the Japanese research team has plans to expand upon this research, thus continuing to contribute to studies worldwide that aim to give scientists the best possible tools with which to obtain a dynamic picture of the brain. As a next step, the team hopes to further elucidate interactions between the various cortical microcircuits that operate in memory encoding. Dr. Miyashita has conjectured that these microcircuits are manipulated by a global brain network. Using the results of this latest study, he and colleagues are poised to further evaluate this assumption. "It will also be important to weave the neuronal circuit mechanisms into a unified framework," said Dr. Hirabayashi," and to examine the effects of learning on these circuit organizations." Equipped with their new view of cortical processing, the team also hopes to trace the causal chain of memory retrieval across different areas of the cortex. "I am excited by the recent development of genetic tools that will allow us to do this," said Dr. Miyashita. A better understanding of object representations from one area of the brain to the next will shed even greater light on elusive aspects of this hierarchical organ

Brain Frontal Lobes Not Sole Center of Human Intelligence, Comparative Research Suggests

May 13, 2013 — Human intelligence cannot be explained by the size of the brain's frontal lobes, say researchers.  Research into the comparative size of the frontal lobes in humans and other species has determined that they are not -- as previously thought -- disproportionately enlarged relative to other areas of the brain, according to the most accurate and conclusive study of this area of the brain.

It concludes that the size of our frontal lobes cannot solely account for humans' superior cognitive abilities.

The study by Durham and Reading universities suggests that supposedly more 'primitive' areas, such as the cerebellum, were equally important in the expansion of the human brain. These areas may therefore play unexpectedly important roles in human cognition and its disorders, such as autism and dyslexia, say the researchers.

The study is published in the Proceedings of the National Academy of Sciences (PNAS) today.

The frontal lobes are an area in the brain of mammals located at the front of each cerebral hemisphere, and are thought to be critical for advanced intelligence.

Lead author Professor Robert Barton from the Department of Anthropology at Durham University, said: "Probably the most widespread assumption about how the human brain evolved is that size increase was concentrated in the frontal lobes.
"It has been thought that frontal lobe expansion was particularly crucial to the development of modern human behaviour, thought and language, and that it is our bulging frontal lobes that truly make us human. We show that this is untrue: human frontal lobes are exactly the size expected for a non-human brain scaled up to human size.

"This means that areas traditionally considered to be more primitive were just as important during our evolution. These other areas should now get more attention. In fact there is already some evidence that damage to the cerebellum, for example, is a factor in disorders such as autism and dyslexia."

The scientists argue that many of our high-level abilities are carried out by more extensive brain networks linking many different areas of the brain. They suggest it may be the structure of these extended networks more than the size of any isolated brain region that is critical for cognitive functioning.

Previously, various studies have been conducted to try and establish whether humans' frontal lobes are disproportionately enlarged compared to their size in other primates such as apes and monkeys. They have resulted in a confused picture with use of different methods and measurements leading to inconsistent findings

Using Anticholinergics for as Few as 60 Days Causes Memory Problems in Older Adults

May 7, 2013 — Research from the Regenstrief Institute, the Indiana University Center for Aging Research and Wishard-Eskenazi Health on medications commonly taken by older adults has found that drugs with strong anticholinergic effects cause cognitive impairment when taken continuously for as few as 60 days. A similar impact can be seen with 90 days of continuous use when taking multiple drugs with weak anticholinergic effect.

The study of 3,690 older adults is among the first to explore how length of use of this group of drugs affects the brain. The study is available online in advance of publication in a print issue of Alzheimer's & Dementia, the journal of the Alzheimer's Association. The research was funded by a grant (R24MH080827) from the National Institute on Aging.

Anticholinergic drugs block acetylcholine, a nervous system neurotransmitter. Drugs with anticholinergic effects are sold over the counter and by prescription. Older adults commonly use over-the-counter drugs with anticholinergic effects as sleep aids and to relieve bladder leakage. Drugs with anticholinergic effects are frequently prescribed for many chronic diseases including hypertension, cardiovascular disease and chronic obstructive pulmonary disease.

A list of drugs noting their anticholinergic burden can be found on the Aging Brain Care website.

The Regenstrief Institute, IU Center for Aging Research and Wishard-Eskenazi Health researchers reported that continuously taking strong anticholinergics, like many sleeping pills or antihistamines, for only 60 days caused memory problems and other indicators of mild cognitive impairment. Taking multiple drugs with weaker anticholinergic effects, such as many common over-the-counter digestive aids, had a negative impact on cognition in 90 days.

"We found that a high anticholinergic burden -- either from one or multiple drugs -- plus two to three months of continuous exposure to that high burden approximately doubled the risk of developing cognitive impairment," said Noll Campbell, Pharm.D., study co-author and Regenstrief Institute investigator. "Millions of older adults are taking sleeping pills or prescription drugs year after year that may be impacting their organizational abilities and memory."

Dr. Campbell is also an IU Center for Aging Research scientist, a research assistant professor in the Department of Pharmacy Practice, Purdue University College of Pharmacy, and a clinical pharmacy specialist in geriatrics with Wishard-Eskenazi Health Services.

"While the link between anticholinergics and cognitive impairment has been reported by our group and others, the cumulative burden of anticholinergics was rather unexpected, as was the lack of a clear association between anticholinergic burden and dementia," said Regenstrief Institute investigator Malaz Boustani, M.D., MPH. Dr. Boustani, the senior author of the study, who is also associate director of the IU Center for Aging Research and an associate professor of medicine at IU School of Medicine. He sees patients at the Healthy Aging Brain Center at Wishard-Eskenazi Health.

"The fact that taking anticholinergics is linked with mild cognitive impairment, involving memory loss without functional disability, but not with Alzheimer's disease and other dementing disorders, gives hope. Our research efforts will now focus on whether anticholinergic-induced cognitive impairment may be reversible," Dr. Boustani said.

Alzheimer's Fuzzy Signals Into High Definition

 May 7, 2013 — Scientists at the Virginia Tech Carilion Research Institute have discovered how the predominant class of Alzheimer's pharmaceuticals might sharpen the brain's performance

17One factor even more important than the size of a television screen is the quality of the signal it displays. Having a life-sized projection of Harry Potter dodging a Bludger in a Quidditch match is of little use if the details are lost to pixilation.

The importance of transmitting clear signals, however, is not relegated to the airwaves. The same creed applies to the electrical impulses navigating a human brain. Now, new research has shown that one of the few drugs approved for the treatment of Alzheimer's disease helps patients by clearing up the signals coming in from the outside world.

The discovery was made by a team of researchers led by Rosalyn Moran, an assistant professor at the Virginia Tech Carilion Research Institute. Her study indicates that cholinesterase inhibitors -- a class of drugs that stop the breakdown of the neurotransmitter acetylcholine -- allow signals to enter the brain with more precision and less background noise.

"Increasing the levels of acetylcholine appears to turn your fuzzy, old analog TV signal into a shiny, new, high-definition one," said Moran, who holds an appointment as an assistant professor in the Virginia Tech College of Engineering. "And the drug does this in the sensory cortices. These are the workhorses of the brain, the gatekeepers, not the more sophisticated processing regions -- such as the prefrontal cortex -- where one may have expected the drugs to have their most prominent effect."

Alzheimer's disease affects more than 35 million people worldwide -- a number expected to double every 20 years, leading to more than 115 million cases by 2050. Of the five pharmaceuticals approved to treat the disease by the U.S. Food and Drug Administration, four are cholinesterase inhibitors. Although it is clear that the drugs increase the amount of acetylcholine in the brain, why this improves Alzheimer's symptoms has been unknown. If scientists understood the mechanisms and pathways responsible for improvement, they might be able to tailor better drugs to combat the disease, which costs more than $200 billion annually in the United States alone.

In the new study, Moran recruited 13 healthy young adults and gave them doses of galantamine, one of the cholinesterase inhibitors commonly prescribed to Alzheimer's patients. Two electroencephalographs were taken -- one with the drugs and one without -- as the participants listened to a series of modulating tones while focusing on a simple concentration task.

The researchers were looking for differences in neural activity between the two drug states in response to surprising changes in the sound patterns that the participants were hearing.

The scientists compared the results with computer models built on a Bayesian brain theory, known as the Free Energy Principle, which is a leading theory that describes the basic rules of neuronal communication and explains the creation of complex networks.

The theory hypothesizes that neurons seek to reduce uncertainty, which can be modeled and calculated using free energy molecular dynamics. Connecting tens of thousands of neurons behaving in this manner produces the probability machine that we call a brain.

Moran and her colleagues compiled 10 computer simulations based on the different effects that the drugs could have on the brain. The model that best fit the results revealed that the low-level wheels of the brain early on in the neural networking process were the ones benefitting from the drugs and creating clearer, more precise signals.

"When people take these drugs you can imagine the brain bathed in them," Moran said. "But what we found is that the drugs don't have broad-stroke impacts on brain activity. Instead, they are working very specifically at the cortex's entry points, gating the signals coming into the network in the first place."

Distorted Thinking in Gambling Addiction: What Are the Cognitive and Neural Mechanisms?

Apr. 8, 2013 — Fascinating new studies into brain activity and behavioural responses have highlighted the overlap between pathological gambling and drug addiction. The research, which is presented at the British Neuroscience Association Festival of Neuroscience (BNA2013) has implications for both the treatment and prevention of problem gambling.

Dr Luke Clark, a senior lecturer at the University of Cambridge (UK), told the meeting that neurocognitive tests of impulsivity and compulsivity, and also positron emission tomography (PET) imaging of the brain have started to show how gambling becomes addictive in pathological gamblers -- people whose gambling habit has spiralled out of control and become a problem.

"Around 70% of the British population will gamble occasionally, but for some of these people, it will become a problem," he said. "Our work has been seeking to understand the changes in decision-making that happen in people with gambling problems. It represents the first large scale study of individuals seeking treatment for gambling problems in the UK, at a time when this disorder is being re-classified alongside drug addiction as the first 'behavioural addiction'. Given the unique legislation around gambling from country to country, it is vital that we understand gambling at a national level. For example, 40% of the problem gamblers at the National Problem Gambling Clinic report that the game they have a problem with is roulette on Fixed Odds Betting Terminals; this kind of gambling machine is peculiar to the British gambling landscape."

In collaboration between the University of Cambridge and Dr Henrietta Bowden-Jones, director of the UK's only specialist gambling clinic in the Central and North West London NHS Trust, Dr Clark and his colleagues compared the brains and behaviours of 86 male, pathological gamblers with those of 45 healthy men without a gambling problem.

"We approach gambling within the framework of addiction, where we think that problematic gambling arises from a combination of individual risk factors, such as genetics, and features of the games themselves. To study individual factors, we have been testing gamblers at the National Problem Gambling Clinic on neurocognitive tests of impulsivity and compulsivity, and we have also measured their dopamine levels using PET imaging," said Dr Clark.

The tests showed that problem gamblers had increased impulsivity, similar to people with alcohol and drug addictions, but there was less evidence of compulsivity. Levels of dopamine -- a neurotransmitter involved in signalling between nerve cells and which is implicated in drug addiction -- showed differences in the more impulsive gamblers.

"Previous PET research has shown that people with drug addiction have reduced dopamine receptors. We predicted the same effect in pathological gamblers, but we did not see any group differences between the pathological gamblers and healthy men. Nevertheless, the problem gamblers do show some individual differences in their dopamine function, related to their levels of impulsivity: more impulsive gamblers showed fewer dopamine receptors," said Dr Clark. "These studies highlight the overlap between pathological gambling and drug addiction.

"To study the properties of the games themselves and how they relate to problem gambling, we have focussed on two psychological distortions that occur across many forms of gambling: 'near-miss' outcomes (where a loss looks similar or 'close' to a jackpot win) and the 'gambler's fallacy' (for example, believing that a run of heads means that a tail is 'due', in a game of chance). In one important discovery, we were the first lab to show that gambling 'near-misses' recruit brain regions that overlap with those recruited in gambling 'wins'. These responses may cause 'near-misses' to maintain gambling play despite their objective status as losses."

Dr Clark said that these findings had implications for both prevention and treatment. "Gambling distortions like the 'near-miss' effect may be amenable to both psychological therapies for problem gambling, and also by drug treatments that may act on the underlying brain systems. By understanding the styles of thinking that characterise the problem gambler, we may also be able to improve education about gambling in teenagers and young adults, to reduce the number of people developing a gambling problem."

The researchers also found a striking demonstration of the underlying brain regions that are involved in gambling when they studied the gambling behaviour of patients who had experienced brain injury due to a tumour or stroke.

"We have seen that two gambling distortions -- the 'gambler's fallacy' and the 'near-miss' effect -- that are evident in the general population, and which appear to be increased in problem gamblers, are actually abolished in patients with damage to the insula region of the brain," he said. "This suggests that in the healthy brain, the insula may be a critical area in generating these distorted expectancies during gambling play, and that interventions to reduce insula activity may have treatment potential.

"The insula is quite a mysterious part of the brain, tucked deep inside the lateral fissure. It is important in processing pain and, more broadly, in representing the state of the body in the brain, and it is striking that gambling is a very visceral, exciting activity. Our ongoing neuroimaging work will look at the relationship between responses in the insula and the body during our gambling tests."

Future work will investigate the styles of thinking that are in evidence when the problem gamblers at the National Problem Gambling Clinic play the simplified games the researchers have developed. "This is the first study to directly look at whether these biases are more pronounced in problem gamblers. We are also starting to recruit the siblings of problem gamblers (those who do not have a gambling problem themselves) in order to look at underlying vulnerability factors," concluded Dr Clark.

This research is funded by grants from the UK's Medical Research Council, and involves further collaboration with researchers at Imperial College London and the University of Oxford.

Non-Invasive Mapping Helps to Localize Language Centers Before Brain Surgery

Apr. 8, 2013 — A new functional magnetic resonance imaging (fMRI) technique may provide neurosurgeons with a non-invasive tool to help in mapping critical areas of the brain before surgery, reports a study in the April issue of Neurosurgery, official journal of the Congress of Neurological Surgeons.


Evaluating brain fMRI responses to a "single, short auditory language task" can reliably localize critical language areas of the brain -- in healthy people as well as patients requiring brain surgery for epilepsy or tumors, according to the new research by Melanie Genetti, PhD, and colleagues of Geneva University Hospitals, Switzerland.

Brief fMRI Task for Functional Brain Mapping
The researchers designed and evaluated a quick and simple fMRI task for use in functional brain mapping. Functional MRI can show brain activity in response to stimuli (in contrast to conventional brain MRI, which shows anatomy only). Before neurosurgery for severe epilepsy or brain tumors, functional brain mapping provides essential information on the location of critical brain areas governing speech and other functions.

The standard approach to brain mapping is direct electrocortical stimulation (ECS) -- recording brain activity from electrodes placed on the brain surface. However, this requires several hours of testing and may not be applicable in all patients. Previous studies have compared fMRI techniques with ECS, but mainly for determining the side of language function (lateralization) rather than the precise location (localization).

The new fMRI task was developed and evaluated in 28 healthy volunteers and in 35 patients undergoing surgery for brain tumors or epilepsy. The test used a brief (eight minutes) auditory language stimulus in which the patients heard a series of sense and nonsense sentences.

Functional MRI scans were obtained to localize the brain areas activated by the language task -- activated areas would "light up," reflecting increased oxygenation. A subgroup of patients also underwent ECS, the results of which were compared to fMRI.

Non-invasive Test Accurately Localizes Critical Brain Areas

Based on responses to the language stimulus, fMRI showed activation of the anterior and posterior (front and rear) language areas of the brain in about 90 percent of subjects -- neurosurgery patients as well as healthy volunteers. Functional MRI activation was weaker and the language centers more spread-out in the patient group. These differences may have reflected brain adaptations to slow-growing tumors or longstanding epilepsy.

Five of the epilepsy patients also underwent ECS using brain electrodes, the results of which agreed well with the fMRI findings. Two patients had temporary problems with language function after surgery. In both cases, the deficits were related to surgery or complications (bleeding) in the language area identified by fMRI.

Functional brain mapping is important for planning for complex neurosurgery procedures. It provides a guide for the neurosurgeon to navigate safely to the tumor or other diseased area, while avoiding damage to critical areas of the brain. An accurate, non-invasive approach to brain mapping would provide a valuable alternative to the time-consuming ECS procedure.

"The proposed fast fMRI language protocol reliably localized the most relevant language areas in individual subjects," Dr. Genetti and colleagues conclude. In its current state, the new test probably isn't suitable as the only approach to planning surgery -- too many areas "light up" with fMRI, which may limit the surgeon's ability to perform more extensive surgery with necessary confidence. The researchers add, "Rather than a substitute, our current fMRI protocol can be considered as a valuable complementary tool that can reliably guide ECS in the surgical planning of epileptogenic foci and of brain tumors."

Spatial Memory: Mapping Blank Spots in the Cheeseboard Maze

Mar. 21, 2013 — IST Austria Professor Jozsef Csicsvari together with collaborators has succeeded in uncovering processes in which the formation of spatial memory is manifested in a map representation.

During learning, novel information is transformed into memory through the processing and encoding of information in neural circuits. In a recent publication in Neuron, IST Austria Professor Jozsef Csicsvari, together with his collaborator David Dupret at the University of Oxford, and Joseph O'Neill, postdoc in Csicsvari's group, uncovered a novel role for inhibitory interneurons in the rat hippocampus during the formation of spatial memory.

During spatial learning, space is represented in the hippocampus through plastic changes in the connections between neurons. Jozsef Csicsvari and his collaborators investigate spatial learning in rats using the cheeseboard maze apparatus. This apparatus contains many holes, some of which are selected to hide food in order to test spatial memory. During learning trials, animals learn where the rewards are located, and after a period sleep, the researchers test whether the animal can recall these reward locations. In previous work, they and others have shown that memory of space is encoded in the hippocampus through changes in the firing of excitatory pyramidal cells, the so-called "place cells."

A place cell fires when the animal arrives at a particular location. Normally, place cells always fire at the same place in an environment; however, during spatial learning the place of their firing can change to encode where the reward is found, forming memory maps.

In their new publication, the researchers investigated the timescale of map formation, showing that during spatial learning, pyramidal neuron maps representing previous and new reward locations "flicker," with both firing patterns occurring. At first, old maps and new maps fluctuate, as the animal is unsure whether the location change is transient or long-lasting. At a later stage, the new map and so the relevant new information dominates.

The scientists also investigated the contribution of inhibitory interneuron circuits to learning. They show that these interneurons, which are extensively interconnected with pyramidal cells, change their firing rates during map formation and flickering: some interneurons fire more often when the new pyramidal map fires, while others fire less often with the new map. These changes in interneuron firing were only observed during learning, not during sleep or recall. The scientists also show that the changes in firing rate are due to map-specific changes in the connections between pyramidal cells and interneurons. When a pyramidal cell is part of a new map, the strengthening of a connection with an interneuron causes an increase in the firing of this interneuron. Conversely, when a pyramidal cell is not part of a new map, the weakening of the connection with the interneuron causes a decrease in interneuron firing rate. Both, the increase and the decrease in firing rate can be beneficial for learning, allowing the regulation of plasticity between pyramidal cells and controlling the timing in their firing.

The new research therefore shows that not only excitatory neurons modify their behaviour and exhibit plastic connection changes during learning, but also the inhibitory interneuron circuits. The researchers suggest that inhibitory interneurons could be involved in map selection -- helping one map dominate and take over during learning, so that the relevant information is encoded.

Changes in Patterns of Brain Activity Predict Fear Memory Formation

Science News-Mar. 1, 2013 — Psychologists at the University of Amsterdam (UvA) have discovered that changes in patterns of brain activity during fearful experiences predict whether a long-term fear memory is formed. The research results have recently been published in the scientific journal Nature Neuroscience.

Researchers Renee Visser MSc, Dr Steven Scholte, Tinka Beemsterboer MSc and Prof. Merel Kindt discovered that they can predict future fear memories by looking at patterns of brain activity during fearful experiences. Up until now, there was no way of predicting fear memory. It was also, above all, unclear whether the selection of information to be stored in the long-term memory occurred at the time of fear learning or after the event.

Picture predicts pain stimulus
During magnetic resonance brain imaging (MRI), participants saw neutral pictures of faces and houses, some of which were followed by a small electric shock. In this way, the participants formed fear memories. They showed fear responses when the pictures were shown that were paired with shocks. This fear response can be measured in the brain, but is also evident from increased pupil dilation when someone sees the picture. After a few weeks, the participants returned to the lab and were shown the same images. Brain activity and pupil diameter were once again measured. The extent to which the pupil dilated when seeing the images that were previously followed by a shock, was considered an expression of the previously formed fear memory.


Pattern Analysis
In order to analyse the fMRI data, (spatial) patterns of brain activity (Multi-Voxel Pattern Analysis, or MVPA) were analysed. By correlating patterns of various stimulus presentations with each other, it is possible to measure the extent to which the representation of two stimuli is the same. It appears that images that have nothing in common, such as houses and faces, lead to increasing neural pattern similarity when they predict danger. This does not occur when they do not predict danger. This leads to the formation of stronger fear responses. The extent to which this occurs is an indication of fear memory formation: the stronger the response during learning, the stronger the fear response will be in the long term.

These findings may lead to greater insights into the formation of emotional memory. As a result, it is possible to conduct experimental research into the mechanisms that strengthen, weaken or even erase fear memory in a more direct fashion, without having to wait until the fear memory is expressed.

The research is part of the Vici project of Prof. Merel Kindt, which is funded by the Netherlands Organisation for Scientific Research (NWO).

Biological Aging, Seen in Women With Alzheimer's Risk Factor, Blocked by Hormone Therapy

Feb. 13, 2013 — Healthy menopausal women carrying a well-known genetic risk factor for Alzheimer's disease showed measurable signs of accelerated biological aging, a new study has found.
However, in carriers who started hormone therapy at menopause  and remained on that therapy, this acceleration was absent, the researchers said. Hormone therapy for non-carriers of the risk factor, a gene variant called ApoE4, had no protective effect on their biological aging.

"This shows that ApoE4 is contributing to aging at the cellular level well before any outward symptoms of decline become apparent," said Natalie Rasgon, MD, PhD, professor of psychiatry and behavioral sciences at the Stanford University School of Medicine and director of the Stanford Center for Neuroscience in Women's Health. "Yet, estrogen appears to have a protective effect for middle-aged women who are carrying this genetic risk factor."

All people carry two copies of a gene called ApoE. (One copy is inherited from each parent). Like genes for eye or hair color, ApoE comes in more than one version. Some 15 to 20 percent of Americans carry at least one copy of ApoE4, a version that puts them at substantially increased risk for late-onset Alzheimer's disease in comparison with people who are not ApoE4 carriers.

Rasgon is the senior author of a study involving 70 relatively well-educated, high-functioning women. It was published online Feb. 13 in PLOS ONE. First author Emily Jacobs, PhD, is a postdoctoral fellow at Harvard Medical School. When the work took place, Jacobs was associated with the lab of another study co-author, Elissa Epel, PhD, associate professor of psychiatry at the University of California-San Francisco.

"We know from numerous studies that ApoE4 is a major genetic risk factor for cognitive decline, Alzheimer's disease and early mortality," Jacobs said. "We wanted to see whether an accelerated rate of biological aging explained this risk."

Another co-author of the study is Elizabeth Blackburn, PhD, professor of biochemistry and biophysics at UCSF, who won the Nobel Prize in 2009 for her work elucidating the mechanism by which intracellular features called telomeres act as biological clocks.

Telomeres are repeated sequences of alternating chemical units of DNA that cap the ends of each chromosome in every cell of all living creatures from fungi to humans. Their function is analogous to that of the plastic caps ringing the ends of a shoelace: They stabilize chromosomes, keeping them from unraveling and preventing other damage, too. But telomeres themselves are not perfectly stable. The process of cell division, as well as bouts of oxidative stress or inflammation, cause them to shorten. If they reach a point at which chromosomal integrity is challenged, this could give rise to cancer or other malfunction in the cell housing the challenged chromosomes. Evolution has engineered protective mechanisms into such cells so that they die or, at least, lose their ability to divide further. But this evolutionary emergency brake has its downside: It contributes to the slow but steady deterioration that manifests visibly in our aging skin and, less visibly, in all the other bodily organs.

Using telomere shortening as an index of biological aging, the investigators drew blood samples from almost 70 healthy women, most of them between the ages of 45 and 65, who had been on hormone therapy since menopause. These women were randomly divided into two groups. One group remained on hormones, while the second group discontinued therapy.

Blood samples from the volunteers were taken when they first entered the study and again two years later. Jacobs, Rasgon and their colleagues separated white blood cells from each sample, extracted the cells' DNA and measured the length of each woman's telomeres at both time points. Then they calculated the change in telomere length that had taken place over the two-year period.

"Telomere length is relatively easy to measure in blood cells, and it's an emerging marker of biological aging," said Jacobs. "It predicts the incidence of age-related diseases and mortality."

Among the many other assessments the researchers made on these women was their ApoE status. They found that ApoE4 carriers' telomeres were six times as likely as those of non-carriers to undergo significant shortening within the two-year study window. On average, the telomeres of ApoE4 carriers had shortened by an amount equivalent to what might be expected to take a decade, based on other studies of healthy women.

However, hormone therapy effectively zeroed out ApoE4's negative influence on telomere length over time. Carriers who remained on this regimen showed no evidence of telomere shortening.

"Our take-home findings from this study were, first, that ApoE4 carriers are at greater risk of biological aging, which is associated with negative health outcomes and, second, that if you were a postmenopausal ApoE4 carrier, being on estrogen therapy was a good thing for telomere length, an established measure of biological aging at the cellular level," Rasgon said. "This brings us a step closer to being able to identify which women will benefit the most from estrogen replacement therapy."

In 2002, one arm of a large-scale longitudinal trial of women examining hormone therapy was halted due to an unexpected increase in adverse cardiovascular events among women on the therapy. The ensuing publicity resulted in women abandoning the regimen in droves. But the trial subjects among whom these ill effects occurred were women who had begun estrogen treatment years after reaching menopause. Subsequent studies have demonstrated that women who start treatment at menopause or soon afterward may experience some benefit.

Rasgon noted that in addition to timing and ApoE status, the type of estrogen formulation used may prove to be an important determinant of hormone therapy's health impact. She said she expects to publish other work soon concerning the differential effects of different formulations.

Rasgon's graduate student Heather Kenna was another Stanford co-author of the study, which was funded by National Institutes of Health grants (AG22008, RR-00070) and the Robert Wood Johnson Foundation Health and Society Scholars Program.

Parkinson's Treatment Can Trigger Creativity: Patients Treated With Dopamine-Enhancing Drugs Are Developing Artistic Talents

Jan. 14, 2013 — Parkinson's experts across the world have been reporting a remarkable phenomenon -- many patients treated with drugs to increase the activity of dopamine in the brain as a therapy for motor symptoms such as tremors and muscle rigidity are developing new creative talents, including painting, sculpting, writing, and more.


Prof. Rivka Inzelberg of Tel Aviv University's Sackler Faculty of Medicine first noticed the trend in her own Sheba Medical Center clinic when the usual holiday presents from patients -- typically chocolates or similar gifts -- took a surprising turn. "Instead, patients starting bringing us art they had made themselves," she says.

Inspired by the discovery, Prof. Inzelberg sought out evidence of this rise in creativity in current medical literature. Bringing together case studies from around the world, she examined the details of each patient to uncover a common underlying factor -- all were being treated with either synthetic precursors of dopamine or dopamine receptor agonists, which increase the amount of dopamine activity in the brain by stimulating receptors. Her report will be published in the journal Behavioral Neuroscience.

Giving in to artistic impulse Dopamine is involved in several neurological systems, explains Prof. Inzelberg. Its main purpose is to aid in the transmission of motor commands, which is why a lack of dopamine in Parkinson's patients is associated with tremors and a difficulty in coordinating their movements.

But it's also involved in the brain's "reward system" -- the satisfaction or happiness we experience from an accomplishment. This is the system which Prof. Inzelberg predicts is associated with increasing creativity. Dopamine and artistry have long been connected, she points out, citing the example of the Vincent Van Gogh, who suffered from psychosis. It's possible that his creativity was the result of this psychosis, thought to be caused by a spontaneous spiking of dopamine levels in the brain.

There are seemingly no limits to the types of artistic work for which patients develop talents, observes Prof. Inzelberg. Cases include an architect who began to draw and paint human figures after treatment, and a patient who, after treatment, became a prize-winning poet though he had never been involved in the arts before.

It's possible that these patients are expressing latent talents they never had the courage to demonstrate before, she suggests. Dopamine-inducing therapies are also connected to a loss of impulse control, and sometimes result in behaviors like excessive gambling or obsessional hobbies. An increase in artistic drive could be linked to this lowering of inhibitions, allowing patients to embrace their creativity. Some patients have even reported a connection between their artistic sensibilities and medication dose, noting that they feel they can create more freely when the dose is higher.


Therapeutic value Prof. Inzelberg believes that such artistic expressions have promising therapeutic potential, both psychologically and physiologically. Her patients report being happier when they are busy with their art, and have noted that motor handicaps can lessen significantly. One such patient is usually wheelchair-bound or dependent on a walker, but creates intricate wooden sculptures that have been displayed in galleries. External stimuli can sometimes bypass motor issues and foster normal movement, she explains. Similar types of art therapy are already used for dementia and stroke patients to help mitigate the loss of verbal communication skills, for example.


The next step is to try to characterize those patients who become more creative through treatment through comparing them to patients who do not experience a growth in artistic output. "We want to screen patients under treatment for creativity and impulsivity to see if we can identify what is unique in those who do become more creative," says Prof. Inzelberg. She also believes that such research could provide valuable insights into creativity in healthy populations, too.

Better Stroke Care, Everywhere: Study Boosts Local Hospitals' Clotbuster Use

Dec. 20, 2012 — From the moment a stroke occurs, patients must race against the clock to get treatment that can prevent lasting damage. Now, a new study shows the promise -- and the challenges -- of getting them state-of-the-art treatment safely at their local hospital, saving precious minutes.

The results come from an effort that tested methods to improve delivery of a time-sensitive, clot-busting drug in stroke patients at 24 community hospitals across Michigan. To date, clot-busting treatment has been mostly used at larger hospitals.

The research effort was coordinated by members of the University of Michigan Health System's Department of Emergency Medicine, Department of Neurology and Stroke Program, which offered half the hospitals education and round-the-clock treatment assistance by phone. The study was funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.

By the end of the study, the community hospitals across Michigan that had the U-M experts as the "sixth man" on their teams did better at delivering the drug called tPA to eligible patients than those that didn't.

The findings of the randomized controlled trial are published in Lancet-Neurology. They show that community hospitals can indeed improve patients' chances of getting tPA in the first few hours of a stroke, without increased risk of dangerous bleeding.

Data from 22 of the hospitals show that tPA use more than doubled in the 11 hospitals that were randomly chosen to get the extra help, versus a smaller increase in the 11 that didn't. Some hospitals even surpassed national targets for tPA use that large stroke centers don't always reach -- a true game-changing performance.

Across the U.S., less than 2 percent of stroke patients receive tPA -- when more than 11 percent could -- largely because of the time limits on its use and delays in getting patients to a hospital. That's why it's important for community hospitals to offer it.

The investigation, called INSTINCT for INcreasing Stroke Treatment through INterventional Change Tactics, demonstrates that tPA can be used safely and appropriately in the community hospital setting -- and that more work needs to be done to expand public access to the only treatment approved by the U.S. Food and Drug Administration to reverse the effects of stroke. While improvement at the target community hospitals that got the education was statistically significant, it was not as large as hoped for. But the findings suggest that relatively low-cost and low-tech interventions can improve local stroke care.

Lead author Phillip Scott, M.D., a U-M emergency physician and principal investigator of the trial, likens the results to the performance of teams from smaller athletic conferences that beat larger, more celebrated teams, to reach the final stages of the annual NCAA college basketball tournament.

"This study suggests that community hospitals can evaluate and treat enough emergency stroke patients to keep their teams' treatment skills sharp, but are of a size that creates rapid lines of communication and stable physican and nurse teams. This may facilitate rapid, safe stroke diagnosis and care," says Scott, an associate professor of emergency medicine at the U-M Medical School. "Four of the hospitals that received the educational intervention achieved tPA use rates of 5 to 8 percent of all stroke patients, compared to only one of the control hospitals. That's a rate many large medical centers strive to reach."

"This study, while finding only modest improvements, provides encouraging evidence that intensive professional education at community hospitals has the potential to improve the use of tPA in acute stroke care," said Scott Janis, Ph.D., program director at the NINDS. "Importantly, it also lays the groundwork for future strategies that should be explored to develop evidence-based interventions that would improve patient access to this proven therapy following stroke."

How it was done, and more about the results:

The study started by collecting baseline data on stroke treatment from 2005 and 2006 at all the hospitals. After the sites were randomized, the U-M team offered continuing medical education classes at the hospitals, workshops at U-M, and other support, including 24-hour phone consultation availability, to the hospitals chosen to receive the intervention.

All the hospitals were in the lower peninsula of Michigan, and were chosen at random from among hospitals with at least 100 stroke discharges per year. All hospitals that participated stayed in the trial until data collection ended in 2010. Hospitals could hold primary stroke center designation, as granted by the Joint Commission, but could not be tertiary academic comprehensive stroke centers.

In all, 188 tPA treatments occurred among 15,065 stroke patients during the baseline period, and 557 treatments occurred among 25,758 stroke patients from 2007 to 2010. The authors note that tPA use at hospitals nationwide rose somewhat during the study period, due to factors such as insurance reimbursement and new data on tPA's effectiveness at preventing disability.

The INSTINCT study findings were complicated by the fact that one of the hospitals enrolled in the trial became an academic stroke center after starting the study. When it and its matched hospital are excluded from the analysis, the remaining hospitals showed enough of an impact from the educational effort to be statistically significant -- a 105 percent increased use of tPA over baseline.

"We essentially saw a doubling of tPA usage, using standard technologies for education and support. Importantly, the increase was achieved safely," Scott says. "This shows we can translate the knowledge of effective stroke treatment into a community setting." The size of the study, with 557 stroke patients treated after intervention began, makes it one of the largest tPA studies in the world.

More about stroke treatment:

The use of tPA in ischemic stroke has grown around the world in the last decade, but many patients who could get the drug still do not. The "treatment window" for tPA has been seen as three hours from the onset of stroke symptoms, though recent studies suggest patients can see benefit even four and a half hours out. The importance of early treatment, however, cannot be overstated, as patients treated earlier have greater benefits and the drug is not currently FDA-approved for use beyond three hours.

Considering that most stroke sufferers wait more than an hour after symptoms start before they seek help, and that travel time to a tPA-providing hospital is around 30 minutes, that leaves hospitals about an hour to do medical imaging, make a firm diagnosis and initiate tPA treatment.

Patients must then be monitored to check for brain bleeding, and to assess the impact of their stroke. To reliably accomplish this, a system for the care of acute stroke patients must already be in place when a patient arrives at the emergency department.

Patients who don't reach a location where they can received standard tPA treatment in time can still potentially be treated with advanced catheter-based clot removal treatment at a major referral hospital such as U-M. These advanced therapies have a longer time window for treatment, but have not been proven more effective than early standard treatment. The Stroke Program at U-M is participating in multiple trials to improve advanced stroke treatment.

Additional authors: William Meurer, M.D., Shirley Frederiksen, M.S., and Robert Silbergleit, M.D. of U-M Emergency Medicine; John Kalbfleisch, Ph.D., Zhenzhen Xu, Ph.D. and Mary Haan, DrPH of the U-M School of Public Health; and Lewis B Morgenstern, M.D., of U-M Neurology. Morgenstern directs, and Scott, Meurer, Frederiksen and Silbergleit are members of, the U-M Stroke Program.

Funding source: NINDS R01-NS-050372

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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Ø As the body ages, so does the brain, especially the ability to remember declines. There are many reasons that cause memory loss; stress, depression, vitamin deficiency, thyroid problems, medical illnesses, Alzheimer’s disease, or just normal aging memory decline.



Ø Memory screenings are the first step toward finding out if the person has early stages of Alzheimer’s dementia vs another condition vs normal aging memory decline.



Ø It is very important to identify the disease or problem that is causing memory loss. Early detection leads to early treatment, which in turn, leads to improved quality of life



Ø Memory screenings can also let the person know that everything is ok. The screenings could turn out normal and put the mind at ease.



Ø Normal scores on a memory screenings provides a valuable opportunity to establish a baseline score for future comparison



Ø A memory screening is not used to diagnose any particular illness & does not replace consultation with a qualified physician or health care provider



B. What is the process of memory screenings?



Ø A screening consists of a series of questions and tasks that are designed to test memory and thinking ability. These tools are non-invasive, safe, and reliable instruments that are sensitive to even mild brain dysfunction

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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.

Physical Activity May Reduce Alzheimer’s Disease Risk at Any Age

ScienceDaily (Apr. 18, 2012) — Daily physical activity may reduce the risk of Alzheimer's disease and cognitive decline, even in people over the age of 80, according to a new study by neurological researchers from Rush University Medical Center that will be published in the online issue of Neurology, the medical journal of the American Academy of Neurology on April 18.


"The results of our study indicate that all physical activities including exercise as well as other activities such as cooking, washing the dishes, and cleaning are associated with a reduced risk of Alzheimer's disease," said Dr. Aron S. Buchman, lead author of the study and associate professor of neurological sciences at Rush. "These results provide support for efforts to encourage all types of physical activity even in very old adults who might not be able to participate in formal exercise, but can still benefit from a more active lifestyle."

"This is the first study to use an objective measurement of physical activity in addition to self-reporting," said Dr. Aron S. Buchman, lead author of the study and associate professor of neurological sciences at Rush. "This is important because people may not be able to remember the details correctly."

To measure total daily exercise and non-exercise physical activity, researchers from Rush asked 716 older individuals without dementia with an average age of 82 to wear a device called an actigraph, which monitors activity, on their non-dominant wrist continuously for 10 days.

All exercise and non-exercise physical activity was recorded. Study participants also were given annual cognitive tests during this ongoing study to measure memory and thinking abilities. Participants also self-reported their physical and social activities. Study participants were individuals from the Rush Memory and Aging Project, an ongoing, longitudinal community study of common chronic conditions of old age.

Over a mean of 3.5 years of follow-up, 71 participants developed Alzheimer's disease The research found that people in the bottom 10 percent of daily physical activity were more than twice as likely (2.3 times) to develop Alzheimer's disease as people in the top 10 percent of daily activity.

The study also showed that those individuals in the bottom 10 percent of intensity of physical activity were almost three times (2.8 times) as likely to develop Alzheimer's disease as people in the top percent of the intensity of physical activity.

"Since the actigraph was attached to the wrist, activities like cooking, washing the dishes, playing cards and even moving a wheelchair with a person's arms were beneficial," said Buchman. "These are low-cost, easily accessible and side-effect free activities people can do at any age, including very old age, to possibly prevent Alzheimer's."

The number of Americans older than 65 years of age will double to 80 million by 2030. "Our study shows that physical activity, which is an easily modifiable risk factor, is associated with cognitive decline and Alzheimer's disease. This has important public health consequences," said Buchman.

Co-authors of the study from Rush are Patricia Boyle, PhD; Li Yu, PhD; Dr. Raj C. Shah; Robert S. Wilson, PhD; and Dr. David A. Bennett.

The National Institutes of Health, National Institute on Aging, the Illinois Department of Public Health and the Robert C. Borwell Endowment Fund helped fund the study.