Alzheimer’s Study Yields Early Clues
The digital images framed on Dr. Gary Small’s computer screen at UCLA are portraits of a mind in decline, lighted by the mental embers of dying memories.
In their abstract whorls of glowing gray matter, these pictures of the human brain reveal what even a clinical expert like Small normally cannot detect: the first subtle signs of Alzheimer’s disease years before anything seems amiss.
Using an unusually sensitive medical imaging scanner at UCLA’s Brain Mapping Center, Small and UCLA neuropsychologist Susan Bookheimer have demonstrated for the first time that the brains of people at genetic risk of Alzheimer’s disease must work much harder than normal to marshal simple memories.
This heightened, unconscious mental effort occurs long before overt symptoms of the disease appear, at a point when no one would notice anything more out of the ordinary than the normal absent-mindedness of middle age.
Moreover, in retesting the same people two years later, the scientists discovered that those who had had to rack their brains hardest later developed the most severe memory loss.
“Now we have a way of combining genetic risk and brain imaging to track brain functional decline over time,” said Small, a UCLA psychiatrist who is an expert on the neurobiology of aging and Alzheimer’s disease.
Published recently in the New England Journal of Medicine, the new imaging research adds weight to a growing body of medical evidence strongly suggesting that Alzheimer’s disease begins with subtle neural changes decades before any observable symptoms of mental decline. Indeed, the neural changes at work in Alzheimer’s may begin so early in life that they may affect how well someone does in school.
The UCLA study “provides additional evidence that subtle changes in brain function can be observed early in the disease course,” said Dr. Neil Buckholtz, chief of the Dementias of Aging Branch at the National Institute on Aging.
To better understand those at genetic risk of Alzheimer’s disease, Small and his colleagues are using two computerized imaging techniques: positron emission tomography, or PET, which records changes in the brain’s metabolism, and a more experimental technique called functional magnetic resonance imaging, or fMRI, which detects extremely rapid changes in neural blood flow. The techniques give researchers a way to monitor the speed, intensity and extent of neural activity.
By investigating how Alzheimer’s disease changes the way the brain works, they hope to learn how someone can lose his place in time and memory as neurons die and synapses atrophy, stripping the mind of its links to the world it once knew.
So far, their findings suggest that these brain-imaging techniques may be able to predict who will develop the disease so far in advance that treatments--as they become available--can begin before the brain is severely affected.
Several experts have also suggested that the imaging techniques could one day serve as a reliable diagnostic tool for a condition easily confused with other causes of flagging memory and dementia.
Experimental PET scans, for example, reveal that Alzheimer’s causes a distinctive pattern of declining brain metabolism. This is strikingly different from the patterns after stroke damage or degenerative disorders such as Huntington’s disease and Pick’s disease.
Today, however, Alzheimer’s disease is almost impossible to diagnose clinically and all but intractable to treatment, despite a number of new experimental drugs.
Alzheimer’s disease affects 4 million Americans, but that number is expected to approach 14 million by mid-century. So prevalent is the disease among those over 85 that some researchers suspect the disease is a normal consequence of aging and longevity. Yet, like so many other degenerative disorders of the human brain, it is hard to study directly because its effects are at first so subtle and so hard to distinguish from normal behavior.
No one knows what causes the disease and, so far, a definitive diagnosis can be made only after an autopsy, when researchers can detect the telltale amyloid plaques that build up around neurons in the hippocampus and parts of the cerebral cortex. Inside these affected brain cells are unusual twisted filaments of protein called tangles.
Researchers have linked the disease to risk factors ranging from traces of aluminum in drinking water to high-fat diets, lead exposure and a low tolerance for alcohol.
But the most telling link to the disease so far appears to be hereditary.
Signs of Genetic Risk
Alzheimer’s does appear to show up more often in some families. Several genes have been implicated, most notably a gene on chromosome 19 that encodes a protein called apolipoprotein-E, which helps in the distribution of cholesterol.
A common variation of that gene, called APOE-4, increases the likelihood that someone will develop the disease. Although the gene is present in 15% of the population, its presence does not mean the onset of the disease is at all certain.
Even so, recent research at UCLA by Small, Bookheimer, PET pioneer Michael Phelps, fMRI imaging expert Mark Cohen and their colleagues shows that people at higher genetic risk of Alzheimer’s:
* Undergo progressive changes in brain metabolism that become more severe with time, even though memory ability remains unaffected. PET scans of those with the APOE-4 gene revealed significantly lower metabolism in two parts of the brain--the parietal and temporal regions--known to be affected by Alzheimer’s, while other people showed changes only in areas associated with normal aging.
* Suffer diminished brain activity as early as age 20--early enough, perhaps, to have an impact on how well these people do in school. A new PET scan study assessing brain activity, age, genetic risk and educational achievement shows that those with the least education appear to suffer the highest rates of Alzheimer’s disease. They found the greatest disparity in those who had the APOE-4 gene.
* May be acutely aware that memory is failing well before any clinical symptoms can be detected. Adults 50 and older who feel acutely aware of flagging memories are more likely than others to carry the APOE-4 gene that raises the risk of Alzheimer’s disease. Even when memory performance is assessed as normal, someone who has the gene is more likely to complain about memory trouble.
The most recent fMRI study used what Small called a “cognitive stress test” to look for any difference in brain function among those with the APOE-4 gene.
The UCLA researchers tested 30 adults between 47 and 82 who had very mild memory complaints but tested normal on conventional memory tests. Half of them were selected for the study because they had the APOE-4 gene.
Each of them took a simple but demanding memory test while undergoing an fMRI brain scan, learning and then recalling lists of random pairs of words.
Although there was no real difference in how well anyone performed on the memory tests, the researchers discovered that people with the APOE-4 gene showed almost twice as much brain activity in those areas that are known to atrophy later in advanced stages of the disease. Those are the same areas in which PET scans showed reduced metabolic levels.
“That led us to conclude that even before there is any overt sign of a memory problem, their brains look different,” Bookheimer said. “Their brains are working harder to get to the same solution.”
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Robert Lee Hotz can be reached at lee.hotz@latimes.com
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By the Mind’s Dying Light
UCLA researchers studying Alzheimer’s disease are using two innovative medical imaging technologies to document the biochemical signature of the brain in distress. With positron emission tomography (PET), they are discovering how the disease affects brain metabolism. An experimental technique called functional magnetic resonance imaging (fMRI) allows them to see how it changes neural activity.
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The two fMRI scans at top show that people with a gene called APOE-4, associated with a higher risk of Alzheimer’s, have more intense and extensive levels of activity (colored areas) in the frontal, temporal and parietal regions during a memory test. Those with a variant of the same gene called APOE-3 (bottom) do not have to work so hard to perform the same memory tasks.
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Early diagnosis
These six PET scans reveal that Alzheimer’s causes a distinctive pattern of declining brain metabolism. The pattern is different from that caused by stroke damage or degenerative disorders such as Huntington’s disease and Pick’s disease. That leads some researchers to hope that PET imaging can be used to diagnose the disease before symptoms develop, allowing earlier and perhaps more effective treatment. Arrows denote areas of significant atrophy.
Sources: UCLA, New England Journal of Medicine, Hippocrates, Proceedings of the National Academy of Sciences
