Photograph by Ed Jones, AFP/Getty Images
Published July 28, 2011
You can't teach an old brain new tricks—but you can restore its ability to remember the old ones, a new study in monkeys suggests.
Chemicals given to rhesus macaques blocked a brain molecule that slows the firing of the brain's nerve cells, or neurons, as we age—prompting those nerve cells to act young again.
"It's our first glimpse of what's going on physiologically that's causing age-related cognitive decline," said study leader Amy Arnsten, a neurobiologist at Yale University.
"We all assumed, given there's a lot of architectural changes in aged brains ... that we were stuck with it," Arnsten said.
But with the new results, "the hopeful thing is that the neurochemical environment still makes a big difference, and we might be able to remediate some of these things."
Brain's "Sketch Pad" Declines With Age
As the brain gets older, the prefrontal cortex begins to decline quickly.
This part of the brain is responsible for many high-order functions, including maintaining working memories—the ability to keep things on a "mental sketch pad" in the absence of stimuli from an action-based task.
The researchers had previously found that in young brains, nerve cells in the prefrontal cortex excite each other to keep working memories on the brain's slate.
"Those connections depend on the neurochemical environment, [which] has to be just right, like Goldilocks," she said.
But when people get into their 40s and 50s, that part of the brain begins to accumulate too much of a signaling molecule called cAMP, which can stop the cells from firing as efficiently—leading to forgetfulness and distractedness.
The number of seniors in the United States will likely double by 2050, and many of them will struggle to cope with the frenetic information age, according to the study.
Monkey See, Monkey Remember
For their study, Arnsten and colleagues spent years training six rhesus macaques of various ages how to play simple video games that require the use of working memory.
"The youngsters do it great for a long time—they're just like humans," she said.
Once the monkeys had mastered the task, the team made recordings of single neurons firing using a tiny fiber inserted painlessly into the brain—a first in any elderly living animal.
Not surprisingly, the team found that the younger animals' neurons fired often during periods when there were no stimuli. Neurons in the older animals tended to be less active during the same periods, according to the study, to be published tomorrow in the journal Nature.
But when the team administered certain drugs to the older animals via the fibers—including a chemical called guanfacine—the chemicals blocked the cAMP pathways and revved up neural activity.
Memory-Boosting Drug in the Works?
Guanfacine is currently an ingredient in a drug used to treat high-blood pressure in adults. The chemical is also in separate clinical trials to see if it improves working memory in the elderly.
Arnsten added that she and her team led previous studies showing that the drug improved working memory in monkeys, and those results have been repeated by other groups in both monkeys and humans.
She cautions that even if the drug is approved as a brain booster, it's too early to say how much memory improvement a person could expect—"we can't say it [would] bring you back to being a 30-year-old," she said.
Meanwhile, neuroscientist James L. McGaugh, who was not part of the study team, says that the previous studies "did not, as I understand it, provide evidence that the enhanced performance was directly associated with 'restored firing' of the neurons. That was an implication."
Importantly, the evidence of enhanced working memory from the previous studies comes from different methods for administering the drugs than those used in the new study, said McGaugh, a fellow at the Center for the Neurobiology of Learning and Memory at the University of California, Irvine.
And for the new experiment, in which the drugs were delivered directly to the brain, the team didn't show conclusively whether monkeys' working memory got better after treatment—though past studies have shown a link.
Thus, it's still an "open question" whether more nerve cell activity actually caused memory improvements, McGaugh said.
"This is not to question the importance of the findings—just the missing piece of information as I understand their experiments."
Paul Aisen, a neuroscientist and director of the Alzheimer's Disease Cooperative Study at the University of California, San Diego, said the study is "another incremental advance" from a strong group of scientists, but it's "uncertain whether this will have implications for treatment for humans."
That's because "measuring ... firing at the level of a single cell, a neuron, is difficult to extend to human behavior, which is highly complex."
"It's not so much that a monkey is not a human—it's that this kind of single-cell recording is a very isolated aspect of brain function."
Are Brain Boosters Needed?
A bigger question, Aisen added, is whether age-related memory decline really needs drug treatment.
"In the absence of a disease such as Alzheimer's, people [compensate] quite well despite the decline in memory," he said. For example, some elderly people combat forgetfulness by simply writing things down.
But study leader Arnsten argues that the fight against cognitive decline is still crucial for many otherwise healthy people.
"These abilities are critical for managing one's finances, for being able to manage one's medical treatment, and [to] live independently."
Study leader Arnsten receives royalties from the sale of extended-release guanfacine, called Intuniv, for the treatment of attention deficit hyperactivity disorder in children and adolescents. She does not receive royalties for the generic form of guanfacine being used in the clinical trial.
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