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Why Do Our Brains Betray Us?
A New Focus on "Mild Cognitive Impairment"

by Jeff Worley

Photo of Stephen Scheff Stephen Scheff, a professor of anatomy and neurobiology at UK, is focusing his work on mild cognitive impairment, the earliest phase of memory decline.

Detection of the earliest phase of memory decline has become so important that there is now a term used to describe this fairly new research focus: mild cognitive impairment, or MCI.

"This phase is marked by memory complaints that become more pronounced as time goes by," says Stephen Scheff, a professor of anatomy and neurobiology at the Sanders-Brown Center on Aging. Several Sanders-Brown researchers, Scheff among them, are now working to better understand MCI, work that is made possible by the UK ADRC and its control group of volunteers. These participants, many of whom are spouses or relatives of an Alzheimer's victim, are neurologically normal and in the interest of science have volunteered to be research subjects. The control group is headed up by David Wekstein, associate director of Sanders-Brown.

In this group of over 400 people, about half are at high risk of developing Alzheimer's because of their family history—about 30 to 40 percent of cases are thought to be hereditary, according to Markesbery. All of these subjects have agreed to donate their brains after they die (see The BRAiNS Program).

"These participants undergo extensive cognitive testing and represent a unique resource for research into the relation between neuropathologic changes and cognitive performance in aging," Scheff says. He adds that participants in the control group who show significant cognitive changes or who develop dementia continue to be actively followed by the ADRC.

"By studying this normal group of volunteers, we're getting closer to being able to detect the earliest possible onset of the disease, and we believe that with early preventive treatment, we can slow the progression of the disease," he says.

Scheff is among the vanguard of researchers in the country involved in this relatively new NIH initiative. "We can learn a lot from looking at end-stage Alzheimer's, but the focus has shifted somewhat to trying to understand what happens in early stages of the disease." Working with Scheff at Sanders-Brown are Frederick Schmitt and Doug Price, who Scheff characterizes as "an indispensable research tech" who has been with him for 17 years.

Some of these control subjects will begin to show some declines in cognitive ability. "Typically, these are individuals who function normally all day long," Scheff says, "but have a memory problem in one particular area. It's a small loss of memory that might manifest itself in, for example, delayed recall, and we can test this." A standard way to measure possible memory loss is to give the patient a list of words and ask him, five or 10 minutes later, to recall the list. People with MCI show a deficit in delayed recall, Scheff says, and some researchers believe this might be the beginning of Alzheimer's disease.

In addition to talking to people in the control group who report possible slight memory loss, Scheff also gathers neurological evidence of MCI. An expert in brain anatomy, he has performed brain autopsies for the past 16 years at Sanders-Brown.

"I'm a neuroanatomist," Scheff says. "I've been teaching brain anatomy in the College of Medicine here for over 23 years." He is part of the UK autopsy team, which also includes Markesbery, who collect particular pieces of tissue that researchers need to analyze. These tissues are used by UK researchers as well as scientists at other institutions around the country. "We're a brain bank," Scheff says. "We store lots of tissue, and we share it with other ADRCs doing excellent research since we're all working to solve the Alzheimer's puzzle."

Some of the brain tissue Scheff studies comes from people in the control group who have been followed by Sanders-Brown researchers for as long as 10 years. "We go back and review the clinical charts and then combine this data with what we see in their brain tissue. We can then determine whether or not the person had MCI."

Scheff closely studies the brains of those who are determined to have had MCI at the time of death, focusing on what he calls "synaptic connectivity."

"You are born with essentially all the neurons you're ever going to have. What develops is the connectivity, through synapses, between different portions of the brain. You have trillions of synapses, and you lose and regain them every day—your brain is constantly remodeling as you learn new things," Scheff explains.

Early on in this work, he focused on several areas in the cortex, association areas that, like tiny assembly plants, put together a lot of information. These areas are where higher-order learning takes place, Scheff says, and Alzheimer's disease especially likes to attack these parts of the cortex.

Using stereology, a mathematical way to estimate the total number of objects using a 3-D model, Scheff can determine the number of synapses in these association areas. "What we've found is that in Alzheimer's disease there is a significant loss of synapses, and the Alzheimer's brain doesn't seem to be capable of replacing these lost connections." Scheff, with several colleagues at Sanders-Brown, has published papers extensively on this work.

More recently, he has focused on another area of the brain—the hippocampus. This is the curved, elongated ridge of brain tissue located behind the ear that has long been thought of as critical for memory.

"This is the area of the brain used for learning and memory, and it's been in the popular press a lot lately. We've gotten tissue from people in the control group who have died, and some of these individuals were tagged as having mild cognitive impairment. In analyzing their brain tissue, we've found that people with MCI tend to have a significant loss of synapses in the hippocampus."

Being able now to count and measure synapse loss is an important step to understanding the mechanisms of Alzheimer's, but even more important, Scheff says, is to learn why this degradation happens.

"We've been dealing with this research challenge head-on for years here at UK," Scheff says. "We've looked at all kinds of toxins as well as free-radical activity. And a part of my work is to see if there is a relationship between the levels of free radicals and changes in number of synapses.

Echoing Markesbery, Scheff says that prevention remains the key. What can you do to keep synapse activity normal and strong?

"Even though it's true that the highest risk factor for getting Alzheimer's is aging, we've found that if you are well educated and you take care of yourself, even people in their late 80s and 90s don't show the loss of synapses and, therefore, don't necessarily get Alzheimer's," Scheff says. "Everybody used to think that if you live long enough, you're going to get Alzheimer's. We don't believe that anymore.

"The best way to keep your synapses functioning normally is to keep your brain very active—what I call 'low-impact mental aerobics.' In the shower, say your ABCs backwards or do a math problem. Learn a foreign language. Learn to play a musical instrument. And keep as physically healthy as you can."

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For more information about Alzheimer's disease clinical trials at the UK Sanders-Brown Center on Aging, call 859/323-6729 or visit www.mc.uky.edu/coa.

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