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The rapid age-related decline of cognitive function that characterizes Down syndrome could one day be managed like diabetes, if a new study holds up.

In an article published recently in Science Translational Medicine, researchers found they could reverse cognitive deficits in mice with a Down syndrome-like condition by replenishing a brain chemical known as norepinephrine.

Although people with Down syndrome, a hereditary disorder caused by an extra, or third, 21st chromosome, have many cognitive deficits that show early in life, one of the main problems is forming contextual memories: spooling together both sensory information and contextual cues to glean information from novel environments.

The researchers speculate this is because the hippocampus, which integrates the brain's "GPS-type data" with information coming from multiple sensors collected from the environment, doesn't receive the norepinephrine it needs to code the memories. The reason lies with its supplier, the locus coeruleus, a tiny region of the brain some 2,000 cells across that is supposed to keep the hippocampus stocked with the signaling chemical, but which in Down syndrome, it appears, has defects.

This constant lack of norepinephrine could also be behind one of the tragedies of Down syndrome: the blistering speed of mental decay. By 40, many people with the condition show symptoms similar to Alzheimer's dementia.

"Although it's difficult to measure dementia in a person already with cognitive problems," says Ahmad Salehi, M.D., Ph.D., lead author of the study and researcher at the Veterans Affairs Palo Alto Health Care System in Palo Alto, Calif., "there are studies where they try to correct for that." In those studies, Dr. Salehi says nearly 60 percent of folks with Down syndrome in their 40s could also be diagnosed with Alzheimer's. In fact, the two disorders appear to be linked; the 21st chromosome houses the gene APP, which is associated with Alzheimer's risks.

Helping the mice

But, says Dr. Salehi, there might be some hope, and it springs from some very basic learning improvements in mice.

In his study, conducted when he was still a researcher at Stanford University, first Dr. Salehi and his team created mice with what is basically a murine version of Down syndrome: they made them with trisomy 16, carrying an extra fragment of the 16th chromosome. (In mice, the relevant genes cluster on the 16th, not the 21st chromosome, and they can only possess an extra fragment, not a full third chromosome, as the resulting effects would kill them.)

And these trisomy 16 mice, when given norepinephrine, managed to show a strong, but brief, reprieve from their learning disabilities.

For instance, when normal mice are exposed to a sound and then a shock, they learn to associate the noise with the shock: when they hear it, they show signs of fear. Mice with trisomy 16 usually have no problem making the connection between the noise and the pain. However, trisomic mice have significant problems remembering the context they were shocked in -- say, a specific cage -- unless they get a dose of norepinephrine. In Dr. Salehi's study, after dosing, the mice with trisomy 16 learned to pair the context with the memory of shock almost as well as the healthy controls did.

But how long does the effect last? Dr. Salehi isn't sure, but it seems to degrade within two weeks. In another arm of the study, he and his colleagues took mice that had spent some time in separate cages, and introduced them to a new environment (such as a hamster cage). Generally, when this happens, normal mice will gnaw on material to build nests, but trisomy 16 mice won't. When given norepinephrine, the trisomy 16 mice would engage in normal nest-building behavior, but this effect would wear off in about half a month, Dr. Salehi says.

Delivery breakthrough

But to run the study, Dr. Salehi says his main challenge was just delivering the drug. Norepinephrine does not normally cross the blood-brain barrier, so the doctors had to use a pro-drug which could slip through to actually bear the chemical into the brain.

But the pro-drug carried its own dangers: norepinephrine is part of the body's fight-or-flight response, triggered by stress, and the doctors didn't want it released outside the brain where it could tax the heart and cardiovascular system.

The solution was to introduce the pro-drug with carbidopa, a drug that prevents the conversion of the pro-drug into norepinephrine, but which can't itself cross the blood-brain barrier.

But despite the ingenuity of the solution, many challenges remain. Dr. Salehi believes any management of age-related declines in Down syndrome would have to also act on acetylcholine systems, other neurotransmitters that also help the hippocampus function and code memories.

And even then, the treatment wouldn't help with the other deficits in Down syndrome, such as fine motor and language problems. "We only measure limited aspects of cognition in this study," he says. Still, he believes that throughout the life of a person with Down syndrome, the cumulative effects of not receiving the right contextual information by not having adequate levels of norepinephrine in the brain could lead to general cognitive disorders. "One idea is this could lead to failure in learning and memory," he says.