In-vivo Banner, Vol 3 No12, Nov/Dec 2004 co branded with the Columbia University Medical Center logo


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NEUROSCIENCE

Complex Brain Circuits May
Protect Against Alzheimer's

Imaging techniques are being used to learn why the more active brain can compensate against the disease's damage

brain network illustration with highlighted spots of activity
These highlighted spots of activity represent a brain network. People with more cognitive reserve may use such networks more efficiently or use alternative networks to deal with Alzheimer's pathology.

An enduring mystery of one of the most insidious brain diseases of modern times – Alzheimer's disease – is why some people succumb to the disease and others either do not or have later onset. One hypothesis maintains that those who seem to be better able to withstand Alzheimer's assault have greater "cognitive reserve" – additional brain circuits that become active when other parts of the brain become too damaged by the plaques and tangles of the disease to function. This hypothesis is increasingly supported by brain imaging studies conducted by Yaakov Stern, Ph.D., professor of clinical neuropsychology in psychiatry.

The hypothesis that cognitive reserve might exist goes back to 1989, when the Annals of Neurology published a perplexing finding. While autopsies of nearly 150 residents of one nursing home showed that the brains of those with Alzheimer's were filled with the characteristic plaques and tangles, about 10 of those autopsied had never exhibited Alzheimer's symptoms while alive despite having about the same number of plaques and tangles. In fact, when compared with residents who had no brain pathology at all upon autopsy, the group with plaques and tangles but no Alzheimer's symptoms scored in the top-fifth percentile on cognitive tests administered before they died.

Other studies subsequently have found that between 25 percent and 67 percent of people whose brains on autopsy show enough characteristics to warrant a postmortem diagnosis of Alzheimer's actually display few of the disease's clinical symptoms while alive. To explain this phenomenon, researchers theorized that the brains of these people are able to compensate for damage in some way.

Although initially skeptical of the existence of cognitive reserve, Dr. Stern is now a leading proponent of its role in Alzheimer's. "Even though we know that at some point the pathology of Alzheimer's overpowers cognitive reserve, there's enough evidence to show that it is a meaningful concept," he says. "Now we're trying to use brain imaging to understand what cognitive reserve actually is. If we can understand how the brain compensates for its deficits, we may find a way to slow the disease. Even slowing Alzheimer's by a couple of years could have a major impact on quality of life of both the individual and his or her family, who are usually the caregivers."

How does cognitive reserve develop?

In a study published in 1994 in JAMA, Dr. Stern presented strong evidence – based on findings from a Columbia study of Washington Heights residents aimed at finding Alzheimer's genes – that education and occupational attainment reduced the risk of developing Alzheimer's, at least for a while. Those who both attended college and attained high job status seemed to have the least risk. Other researchers have confirmed these results; Dr. Stern and others have extended the findings to include IQ levels and degree of participation in leisure activities, such as games and social events. He cautions, however, that greater cognitive reserve does not make an individual immune to Alzheimer's. "The pathology is there and it can happen to anyone," he says. "Education modulates the impact of the pathology but does not prevent it."

How might cognitive reserve preserve brain function?

One theory suggests that an individual who has a greater number of neurons and synapses when he or she develops Alzheimer's can afford to lose more of those neurons and synapses before symptoms manifest. While some evidence also suggests that people with larger brains are less likely to become demented, Dr. Stern is investigating the possibility that cognitive reserve has more to do with how people use their brains than how much brain they have. In other words, reserve may derive from the brain's "software," not its "hardware."

Dr. Stern's laboratory is one of the few in the world that has turned to brain imaging techniques to measure the activity of all parts of the brain simultaneously. Instead of looking for differences in how people use individual regions of the brain, he is searching for differences in the use of entire networks distributed throughout the brain.

"A brain network is like an Alexander Calder mobile where all the parts are interrelated," he says. "When one part of the mobile moves up, another moves down. When the brain works, different areas of the brain 'talk' to each other, so some parts will be active, and other parts less active."

Dr. Stern and his colleagues are testing two possible ways neuronal networks may underlie cognitive reserve. In one case, people with greater cognitive reserve may have the ability to switch to, or even create, alternate networks required to complete a task. "Think of a child who's just starting out learning math," he says. "That child might think the only way to solve the problem of 12 plus 9 is by adding 2 and 9 and carrying the 1, But someone with more experience can solve it another way, by first adding 12 and 8 and then adding the leftover 1."

Another possibility is that the brain circuitry in people with more reserve somehow functions more efficiently. So far, it seems that reserve may be a mixture of both – greater plasticity, or flexibility, and greater efficiency. Using PET imaging, Dr. Stern has found in one study that when given the task of trying to remember a list of words, healthy older people use a different brain circuit than Alzheimer's patients. But a few Alzheimer's study participants used the same network as the healthy elders. Those with high activity in this network remembered more words, indicating that people who can activate the network to a greater degree may also have more reserve.

Can cognitive reserve be boosted?

Once researchers learn how cognitive reserve might delay the onset of Alzheimer's symptoms, Dr. Stern hopes that some sort of training program could be devised to boost a patient's reserve in the early stages and thus slow the progression of the disease.

At the moment, however, it is still unclear just what that training should entail. "People ask me all the time: Should I learn how to juggle? Should I take an enrichment course of one type or another?" Dr. Stern says. "But we haven't figured out what's best, or how much people need, or even when they have to start. We still have a lot to learn about this disease."

This work is supported by the Alzheimer's Association and the NIH.

—Susan Conova 


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