Neuroscience

Alzheimer’s disease is the most common cause of late-life dementia. The disorder is thought to be caused by a protein known as amyloid-beta, or Abeta, which clumps together in the brain, forming plaques that are thought to destroy neurons. This destruction starts early, too, and can presage clinical signs of the disease by up to 20 years.

For decades now, researchers have been trying, with limited success, to develop drugs that prevent this clumping. Such drugs require a “target” — a structure they can bind to, thereby preventing the toxic actions of Abeta.

Now, a new study out of UCLA suggests that while researchers may have the right target in Abeta, they may be missing the bull’s-eye. Reporting in the Jan. 23 issue of the Journal of Molecular Biology, UCLA neurology professor David Teplow and colleagues focused on a particular segment of a toxic form of Abeta and discovered a unique hairpin-like structure that facilitates clumping.

"Every 68 seconds, someone in this country is diagnosed with Alzheimer’s," said Teplow, the study’s senior author and principal investigator of the NIH-sponsored Alzheimer’s Disease Research Center at UCLA. "Alzheimer’s disease is the only one of the top 10 causes of death in America that cannot be prevented, cured or even slowed down once it begins. Most of the drugs that have been developed have either failed or only provide modest improvement of the symptoms. So finding a better pathway for these potential therapeutics is critical."

The Abeta protein is composed of a sequence of amino acids, much like “a pearl necklace composed of 20 different combinations of different colors of pearl,” Teplow said. One form of Abeta, Abeta40, has 40 amino acids, while a second form, Abeta42, has two extra amino acids at one end.

Abeta42 has long been thought to be the toxic form of Abeta, but until now, no one has understood how the simple addition of two amino acids made it so much more toxic than Abeta40.

In his lab, Teplow and his colleagues used computer simulations in which they looked at the structure of the Abeta proteins in a virtual world. The researchers first created a virtual Abeta peptide that only contained the last 12 amino acids of the entire 42–amino-acid-long Abeta42 protein. Then, said Teplow, “we just let the molecule move around in a virtual world, letting the laws of physics determine how each atom of the peptide was attracted to or repulsed by other atoms.”

By taking thousands of snapshots of the various molecular structures the peptides created, the researchers determined which structures formed more frequently than others. From those, they then physically created mutant Abeta peptides using chemical synthesis.

"We studied these mutant peptides and found that the structure that made Abeta42 Abeta42 was a hairpin-like turn at the very end of the peptide of the whole Abeta protein," Teplow said.

The hairpin turn structure was not previously known in the detail revealed by the researchers, “so we feel our experiments were novel,” he said. “Our lab is the first to show that it is this specific turn that accounts for the special ability of Abeta42 to aggregate into clumps that we think kills neurons. Abeta40, the Abeta protein with two less amino acids at the end of the protein, did not do the same thing.”

Hopefully, the work of the Teplow laboratory presents what may the most relevant target yet for the development of drugs to fight Alzheimer’s disease, the researchers said.

Chronic drinking is known to have detrimental health effects such as cardiac and liver problems, cognitive impairments, and brain damage. Binge drinking in particular is known to increase the risk of developing dementia and/or brain damage, yet little is known about an exact threshold for the damaging effects of alcohol. A study using rodents to examine various markers of neurodegeneration has found that brain damage can occur with as little as 24 hours of binge-like alcohol exposure.

Results will be published in the March 2013 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"We know that the extent of damage following alcohol exposure depends heavily on the manner in which it is consumed," said Kimberly Nixon, associate professor of pharmaceutical sciences at The University of Kentucky as well as corresponding author for the study. "Human studies suggest that binge-pattern drinking is more closely associated with brain damage. One study, for example, reported that binge drinking at least once per month in adulthood significantly increases the risk of developing dementia later in life. Animal models help provide the critical information that binge drinking, which produces high blood alcohol levels, directly causes damage."

"The exact threshold for the damaging effects of alcohol on the brain is unclear," commented Fulton T. Crews, John Andrews Distinguished Professor and director of the Center for Alcohol Studies at the University of North Carolina. "It is likely that the higher the blood alcohol level the greater the damage, however, this manuscript only studies binge drinking, using vimentin and flurojade B as markers of neurotoxicity."

"People hear from multiple sources that low-moderate alcohol consumption can be beneficial, and then we come along and say that heavy alcohol use leads to detrimental outcomes," said Nixon. "People then want to know what the line is between beneficial and detrimental Unfortunately, we don’t know exactly. However, our study suggests that it may be even less than previously thought."

Nixon and her colleagues administered a nutritionally complete liquid diet to adult male Sprague-Dawley rats that additionally contained either alcohol (25% w/v) or isocaloric dextrose every eight hours for either one or two days. The rodents were sacrificed immediately following, two days after, or seven days after alcohol exposure and their brain tissues were examined.

"This was really a simple study that took advantage of some new ‘tools’ to look for evidence of brain damage," explained Nixon. "In other words, we didn’t look for dying cells themselves, but we looked at more indirect indices of damage by looking at what happens to astroglia, one of the ‘supporting’ cells for neurons. Astroglia react to brain damage by expressing several proteins that they do not normally express under healthy, happy conditions, one of which is an intermediate filament protein called vimentin. We saw a remarkable number of cells expressing this marker It is one of those ‘here is your brain, here is your brain on drugs’ kind of findings where the expression was obvious to the naked eye in many brains with as little as 24 hours of high blood alcohol levels."

Nixon added that, because rodents metabolize alcohol significantly faster than humans do, it is important to look at the actual concentration of alcohol in the blood in order to translate this to the human condition. “These rats had blood alcohol levels that were more than four times the legal driving limit, which for humans would require excessive drinking in the nature of a 12-pack of beer, a couple bottles of wine, or half of fifth of whisky. Unfortunately, drinking self-reports and blood alcohol level data from emergency rooms confirm that this level of drinking is common in those with alcohol use disorders.”

"Rodent brain damage can model human damage," noted Crews. "Vimentin seems to be a good marker of glial activation that shows that one day of binge drinking can cause some brain damage that persists and grows after a week of abstinence. However, both rodent and human brain damage generally require long-term alcohol consumption that models alcoholism and not the acute responses studied in this manuscript."

Nixon agreed. “The lack of overt neuronal deterioration suggests that a single, short-term, high-level binge probably does not result in functional changes and/or cognitive deficits,” she said. “However, since alcoholics experience multiple binges throughout their lifetime, it is important to consider that each successive binge, starting with the very first one, affords some level of damage to the brain. Therefore, theoretically, with multiple binges comes a cumulative detrimental effect where pronounced cognitive, behavioral, and structural effects are observed.”

Nixon said this study demonstrates that new discoveries are always possible. “You have to know where and when to look for some of these effects,” she said. “The reason why this discovery wasn’t made previously is merely due to groups, ourselves included, not taking the time to thoroughly investigate these lower threshold doses with some pretty specific time points. Chasing down a threshold is not a sexy topic and it was actually fairly risky in that it was possible that we would have had all negative effects. Nonetheless, the take-home message of our data is that even one short-duration binge-alcohol experience – which is unfortunately similar to what young adults may experience during spring break or weekend partying - may start a cascade that leads to brain damage.”

Adolescent boys with attention deficit hyperactivity disorder (ADHD) are more likely to be shorter and slimmer than their same-age peers, according to a new study published in the Medical Journal of Australia today.

Dr Alison Poulton from the University of Sydney and her coauthors investigated the influence of stimulant medication on the growth and physical development during puberty of adolescent boys with ADHD.

The study found that prolonged treatment for more than three years with stimulant medication was associated with a slower rate of physical development during puberty.

"Our findings suggest that stimulant medication delays the rate of maturation during puberty, including the timing of the peak growth rate, but not the onset of puberty," said Dr Poulton, from Sydney Medical School.

"To maintain an adequate rate of growth during puberty we recommend that boys on ADHD stimulant medication should take the lowest dose that adequately treats their ADHD," said Dr Poulton.

The researchers recruited 65 boys aged between 12 and 16 years who had ADHD and had been on stimulant medication for more than three years. Compared with boys without ADHD, boys aged between 12 and 14 years with ADHD had significantly lower weight and body mass index, and those aged between 14 and 16 years with ADHD had significantly lower height and weight.

There was no difference in pubertal development between boys with and those without ADHD aged between 12 and 14 years, but those aged between 14 and 16 years with ADHD showed significant delay.

The study also found there was a significant inverse relationship between the dose of stimulant medication and the growth rate among boys aged between 14 and 16 years with ADHD.

The authors found that boys who had taken stimulant medication for ADHD for a minimum of three years until 14 years of age showed slower weight gain but comparable height and physical development related to puberty to boys of the same age without ADHD.

However, boys aged between 14 and 16 years with ADHD were significantly behind their peers in height and pubertal development.

Attention Deficit Hyperactivity Disorder (ADHD) is the most common childhood neuropsychiatric disorder. Yet there is currently no tool that will confirm the diagnosis of ADHD. In her thesis entitled “Development of a genotyping system to be applied in Attention Deficit Hyperactivity Disorder and its Pharmacogenetics” (“Desarrollo de un sistema de genotipado para la aplicación en el ‘trastorno por déficit de atención con hiperactividad’ y su farmacogenética”), the researcher Alaitz Molano, a graduate in biochemistry and PhD holder in Pharmacology from the UPV/EHU-University of the Basque Country, presents a tool that could improve not only the diagnosis of but also the therapeutics for this disorder.

The prevalence of ADHD is between 8% and 12% among the infant-adolescent population worldwide, and 50% continue with the symptoms into adult life. Children with ADHD have difficulty paying attention, do not complete the tasks they have been assigned and are frequently distracted. They may also display impulsive behaviour and excessive, inappropriate activity in the context they find themselves in, and experience great difficulty restraining their impulses. “All these symptoms seriously affect the social, academic and working life of the individuals, and impact greatly upon their families and milieu close to them,” says Molano.

In view of the problems existing in diagnosing ADHD patients and deciding about their treatment, this PhD thesis set out to develop and clinically validate a genotyping tool that could help to confirm the diagnosis, to predict how it will evolve, and to select the most suitable pharmacological treatment in each case.

Molano studied how genetic polymorphisms (variations in the DNA sequence between different individuals) are associated with ADHD. “We looked for all the associations that had been described previously in the literature worldwide, and did a clinical study to see whether these polymorphisms also occurred in the Spanish population; the reason is that genetic associations vary a lot between some populations and others.”

About 400 saliva samples of patients with ADHD and a further 400 samples from healthy controls without a history of psychiatric diseases were analysed. And the use of over 250 polymorphisms led to the discovery of 32 polymorphisms associated not only with the diagnosis of ADHD but also with the evolution of the disorder, with the ADHD subtype, the symptomatological severity and the presence of comorbidities.

On the basis of these results, Molano is proposing a DNA chip with these 32 polymorphisms, which could be updated with new polymorphisms, as a tool not only for diagnosing but also for calculating genetic susceptibility to different variables (responding well to drugs, normalisation of symptoms, etc.).

The study has also confirmed the existence of the 3 ADHD subtypes: lack of attention, hyperactivity, and a combination. “It can be seen that on the basis of genetics the children that belong to one subtype or another are different,” explains Molano.

By contrast, no direct associations were found between the polymorphisms analysed and the response to pharmacological treatment (atomoxetine and methylphenidate). Molano believes that this could be due to the fact that “in many cases the data on drugs we had available were not rigorous,” due to the difficulty in collecting data of this kind. Molano will in fact be pursuing her research along this line: “We want to concentrate on the drug response aspect, obtain more, better characterised samples, and monitor the variables in the taking of drugs very closely, whether they were actually being taken or not, etc.”

Molano hopes that this tool will reach the clinics: “The project was funded by Progenika Biopharma and the pharmaceutical company JUSTE SAFQ, but we also have another 10 collaborating clinics belonging to public and private centres in Spain, and it’s tricky getting them all to agree on matters like patents, marketing, etc. But our idea is that it should eventually be marketed and be welcomed.”

Scientists at the University of Birmingham have devised a unique screening instrument that provides a ‘one-stop’ brain function profile of patients who have suffered stroke or other neurological damage.

The Birmingham Cognitive Screen (BCoS) can offer a visual snapshot of the cognitive abilities and deficits of an individual which can then be used to guide clinical decision making.

Following brain damage, including stroke, head injury, carbon monoxide poisoning and degenerative change, people can experience a range of cognitive problems as well as difficulty with physical movement. Cognitive problems strongly influence a patient’s ability to recover but patients are not routinely screened to detect them.

The first test of its kind, BCoS has been designed by a team of brain experts co-ordinated by Research Fellow Dr Wai-Ling Bickerton (also a chartered psychologist and occupational therapist) at the University of Birmingham in collaboration with Professors Glyn Humphreys and Jane Riddoch at Oxford University and Dana Samson at Louvain University.

Comprising a user-friendly manual, a test book, a CD containing Auditory Attention Test stimuli, a supply of examiner and examinee booklets and a zip-up pouch of test objects, the test takes 45-60 minutes and is carried out by trained health professionals and covers a range of cognitive abilities, including attention, executive function, spatial awareness, speech and language processing, action planning and control, memory, and number processing.

‘Through research outcomes supported by the Stroke Association, BCoS has already been used to successfully assess more than 1,000 stroke survivors in the West Midlands,’ explains Dr Bickerton. ‘BcoS has been validated against “standard” neuropsychological tests and assessed against measures of cognition and activities of everyday living for patients in the chronic stage.

‘The test has been designed to be highly inclusive and, as such, is an optimal tool for most stroke survivors regardless of the cognitive effects of stroke,’ she says. ‘It is also applicable to individuals with brain injury or dementia. 

A Queen’s University study is giving new insight into how the neurons in our brains control our limbs. The research might one day help with the design of more functional artificial limbs.

“We’ve taken a step closer to understanding how our arms and legs work and how we move our bodies,” says neuroscience researcher Tim Lillicrap, who worked with neuroscience professor Stephen Scott on the study.

The researchers used a novel network model, coupled with a computer biophysics model of a limb, to explain some of the prominent patterns of neural activity seen in the brain during movements.

The findings refine previous notions of how neurons in the primary motor cortex fire and drive muscles. The primary motor cortex is the region of the brain that sends the largest number of connections to the spinal cord.

When moving an arm or a leg, nerve impulses are sent along nerve fibres to control the movement of limbs. Different movements require different patterns of nerve impulses — the relationship between these neural patterns and the resulting movements is poorly understood.

The study demonstrates that the patterns of activity are related to specific details of limb physics — for example, the patterns of neural activity are tuned (or optimized) for muscle architecture and limb geometry.

Dr. Lillicrap, who did the study as part of his PhD thesis at Queen’s and is now a post-doctoral fellow at Oxford University in England, says better understanding of how the brain controls limbs will help develop artificial limbs in the future.