Friday July 29 2011
The drugs were tested in six monkeys of different ages
“Memory decline reversed in tests on monkeys,” reported The Daily Telegraph. The newspaper went on to say that “a cure for memory loss in middle and old age could be a step closer thanks to a drug which restores the brain to a more youthful state”.
This news story is based on research examining differences in the rate at which brain cells fired in monkeys of various ages. It then looked at the effect of several drugs on these rates. The researchers found that the rate of firing of specific brain cells decreased in older monkeys. After being given some of the drugs, the brain cell firing frequency in middle age and older adults increased.
The researchers say the continuous firing of these brain cells is needed for ‘working memory’; a type of memory essential for abstract thought and completing complicated tasks.
This was an interesting and well-conducted animal study that could have important implications for addressing age-related memory loss. However, much further research is needed before we can be confident that the results apply to humans and can be used as a treatment for memory loss.
Where did the story come from?
The study was carried out by researchers from Yale University in the US and was funded by the National Institute of Aging, a part of the US National Institutes of Health.
It was published in the peer-reviewed medical journal Nature.
The lead researcher and Yale University receive royalties from Shire Pharmaceuticals from the sales of extended-release guanfacine, a version of the drug used in this study.
Generally, the media reported the story accurately. Although much of the focus was on guanfacine, many other drugs were also included in the study.
What kind of research was this?
This was an animal study that examined the effect of a drug called guanfacine on working memory in middle aged and elderly monkeys. Working memory is responsible for retaining information that is no longer available. The ability to do this is essential for abstract thought and completing complicated tasks. The researchers say that tasks requiring working memory include summoning information from long-term memory, such as where you left your keys, or remembering a recent event, such as a new phone number.
This particular animal model was chosen because previous research has found that working memory starts to decline in middle age in both humans and monkeys.
The researchers looked at whether normal ageing alters the functioning of brain cells in a part of the brain called the prefrontal cortex, which is responsible for working memory. Successful working memory is believed to require continuous communication between brain cells in this region.
Changes in the chemical environment in this region can alter the number of times prefrontal cortex brain cells ‘fire’ (communicate with each other) by weakening the connections between the cells. It is thought that the less frequently these cells fire, the less reliable an individual’s working memory will be. Researchers believe that a particular molecule, called cAMP, keeps these brain cells from firing.
Animal studies are useful ways to conduct preliminarily research that could not be carried out in humans. Follow up clinical trials are needed before the results can be confirmed to apply to humans.
What did the research involve?
The researchers compared the frequency of brain cell firing in the prefrontal cortex during working memory tasks in young adult, middle age and elderly monkeys. They studied the performance of six monkeys: two young adults, two middle age, and two elderly monkeys, on working memory tasks which required them to remember the location of an object.
The researchers recorded the brain activity of each monkey during this task and measured the firing frequency in different types of brain cells. These measurements were used to compare the level of firing across the three age groups, and to establish a starting rate in each age group. Following this, the monkeys were treated with different drugs, and the firing rates were measured again and compared against these starting firing rates.
The researchers wanted to see whether treatment with the multiple drugs could increase the frequency with which the brain cells fired. They tested drugs that are known to decrease the action of cAMP, increase the action of cAMP, or attach to the parts of brain cells that cAMP acts on. The drugs were applied to the monkeys’ brains, and the same task was repeated while the researchers recorded the brain activity and measured the frequency with which the brain cells fired.
The researchers compared the firing frequency data from the first set of experiments to establish whether there were any differences between the different age groups. They then compared the data from the second set of experiments to data from the first set of experiments, to establish whether or not the drugs had any impact on brain cell activity while the monkeys were performing tasks that needed them to use working memory.
The working memory tasks used during this study are commonly used in both animal and human studies.
What were the basic results?
During the initial task, which required the monkeys to remember the physical location of an object, the researchers found that the older the monkey, the less frequently their brain cells fired. That is, the young adult monkeys’ brain cells fired the most frequently, and the elderly monkeys’ brain cells fired the least frequently. The change in firing rate was only found to occur in the brain cells that fire when the object was no longer present, as opposed to those brain cells that are responsible for recognising the presence of the object and therefore fire while the object was present.
When the same task was performed after the application of the different drugs, the researchers found that after being given the drugs that decrease the action of cAMP, the brain cell firing frequency in middle age and older adults increased. When drugs that increase the action of cAMP were used, the brain cell firing frequency decreased.
How did the researchers interpret the results?
The researchers say their results show a ‘physiological basis for age-related working memory decline in the primate brain’, and that this decline can be reversed through treatment of the brain’s chemical environment. They go on to say that ‘there is potential to restore at least some cognitive abilities in the elderly.’
This was a well-conducted animal study that examined the functional basis for a specific type of age-related memory loss. Research into memory and age-related memory loss is increasingly important as our society continues to age. However, results from animal studies, while promising, still need to be interpreted cautiously.
It is unclear at this point whether the drug used in this research will work the same way in humans. Well-designed clinical trials will be able to examine the impact of the drug on memory loss in humans. However, until the results of such trials are available, how much this study can apply to human memory loss is unclear.
Several other aspects of this study, and the interpretation of its results, are important to note:
- The study did not focus on comparing how well the monkeys actually performed the memory tasks, either between age groups or after the drugs were given. Rather, it focused on measuring brain activity, which is thought to be related to task performance. To get an accurate idea of the real effects of the drugs on monkeys of different ages, future studies will need to measure effects on task performance directly. Any such effects in monkeys may not carry over – or carry over safely – to humans. In short, there is a long way to go before this has a practical human application.
- The drug guanfacine mentioned in news reports, is not the only drug studied with beneficial effects. Other drugs that either decreased the action of cAMP, or blocked the specific part of the brain cell on which cAMP acts, also improved the firing frequency in older monkeys.
- In this study, the drugs were applied directly into the brain region, not taken in pill or injection form. This is clearly not feasible in humans, and whether or not the drug will have the same impact when delivered differently remains to be seen. However, the researchers do say that previous research has shown that guanfacine enhances working memory performance in animals when the subjects were given the drugs and it was not applied directly to the brain.
- The study only involved six monkeys, which makes the results and the differences found more difficult to interpret. However, as this was a preliminary study that aimed to examine the effect of the drug in principle, and the researchers plan to continue this study in humans in accordance with established clinical trial guidelines, the small sample size is less problematic.
- The type of memory loss examined in this study is a common characteristic of normal ageing, and includes things such as forgetfulness and distractibility. It is not the same as the memory loss seen in specific diseases such as Alzheimer’s disease.