A new test can detect the disease in early stages. How will it benefit patients?
The way doctors diagnose Alzheimer's may soon change. Today, doctors rely on memory and reasoning tests and reports of social withdrawal to identify Alzheimer's patients. Such assessments by experts can be quite decisive, but they are not completely reliable. About one in five people diagnosed with this degenerative disease of the nervous system actually suffers from another type of insanity (dementia), or a completely different problem, such as depression. To know for sure that someone has Alzheimer's, doctors have to remove small pieces of brain, examine the cells under a microscope and count the number of clumps of proteins called amyloid plaques. A particularly high number of plaques is an important telltale sign of Alzheimer's. But since such a procedure can further impair the mental skills of patients, it is almost always performed only at post-mortem.
However, in the past decade, scientists have developed sophisticated brain scans that can estimate the amount of layers in the brains of living people. In the laboratory, such scans have been found to be very effective in studies of the earliest stages of the disease, even before symptoms are apparent. The reliability of the results caused the US Food and Drug Administration (FDA) to approve in 2012 one such test, which is performed using a substance called Amyvid, to help and diagnose patients with memory problems or other cognitive difficulties.
Despite FDA approval, debate continues about how this test should be used, because of doubts about the exact role of amyloids in Alzheimer's disease and because the practical value of the information the scan provides is controversial. Not every person who has an excess of amyloid plaques in their brain develops Alzheimer's, and today there is no way to estimate who will be the unlucky ones who will develop it. Recent studies have shown that in the brains of about a third of the elderly residents whose mental capacity is normal, it is possible to find medium to high levels of layers, without any noticeable negative effect. And mentioning the name of the disease in the absence of symptoms may do more harm than good because there are still no effective treatments.
A new clinical trial will test whether giving an experimental drug immediately after the plaques are diagnosed can slow or stop the development of Alzheimer's. But even if the results are encouraging, it will be years before a new drug reaches the market. In the meantime, doctors must determine how to use the scan responsibly. "The whole field is grappling with this question," says Rayza Sperlind of Brigham and Women's Hospital. She believes that the scan will help facilitate the challenging diagnosis, but "as a test with predictive value, it is still immature.
a sign of trouble
Scientists first linked amyloid plaques with what is now known as Alzheimer's disease more than 100 years ago. In 1906, the German psychiatrist Alois Alzheimer documented unusual protein aggregates in the brain of a demented patient who had died. By the mid-80s, scientists realized that these plaques were composed of a protein called amyloid-beta.
Normal nerve cells produce a large amount of amyloid-beta, but the role of the protein remains a mystery. In the early stages of Alzheimer's disease and other degenerative diseases of the nervous system, these proteins start to behave strangely: they stick to each other and form clumps that keep growing. Scientists are still unsure whether these plaques are responsible for the fatal loss of millions of nerve cells that characterizes Alzheimer's disease, or whether they are a byproduct of some other, unknown cause.
Nevertheless, the accumulations are formed long before the appearance of the first obvious signs of the madness, and multiple layers remain one of the most successful markers of the disease. Neurologists John S. Morris, Randall Bateman and their colleagues at Washington University in St. Louis are following the condition of healthy carriers of a rare genetic mutation that almost certainly causes Alzheimer's at a young age. They identified amyloid plaques in their brains 15 years before cognitive problems appeared.
Attempts to design a scan that could detect amyloid plaques began about 12 years ago at the University of Pittsburgh. Researchers injected patients with a small, harmless amount of a radioactive dye called Pittsburgh compound B, or PIB. The dye reaches the brain through the blood circulation and stains only amyloid aggregates. The brain scan using positron emission tomography (PET) picks up the gamma radiation that is emitted from the dye molecules and produces images that highlight the layers.
Scientists at Avid Pharmaceuticals in Philadelphia relied on Pittsburgh technology to develop the substance Amivid - also a radioactive dye. Amyvid survives longer in the brain and therefore provides doctors with a longer stay to scan their patients. The initial results were so promising that Eli Lilly bought Avid in 2010 for $300 million. Two years later, the FDA approved the use of Amivid in the test, which can now be done at more than 450 imaging centers in the US, usually at a cost of $3,000 or more.
to scan or not to scan
The FDA and the neurology community regard Amivide with enthusiasm mixed with trepidation. Officially, the test was approved mainly to rule out a diagnosis of Alzheimer's in people who already suffer from cognitive impairment, especially when the causes of the impairment are unclear. A team of experts, convened by the American Alzheimer's Association and the Society for Nuclear Medicine and Molecular Imaging, published guidelines in January 2013 that advised limiting the use of the test only to patients with mild and persistent cognitive impairment whose cause is unknown, and to patients who developed delirium at a particularly young age or who suffer from delirium with atypical symptoms, like hallucinations. In such situations it is difficult to determine whether the culprit is Alzheimer's, and Amyvid is exactly the tool that can help. If the scan detects a small number of plaques, doctors can more confidently rule out Alzheimer's and look for other causes, such as a rare, rapid degeneration of the brain's frontal lobes.
The team of experts also advised against amyloid scans in people who do not suffer from cognitive impairment. The experts feared not only that a positive result would worsen particularly vulnerable subjects to depression or even push them to commit suicide, but also that the information would make it difficult for them to get long-term health insurance or renew their driver's license, says Jason Carlwisch, a member of the expert team and a professor of medicine and medical ethics at the University of Pennsylvania.
Despite these warnings, which are only supported by the Eli Lilly company, many people in the scientific community have reservations. A member of the expert team, neurologist Norman Foster of the University of Utah, fears that some doctors and patients will rely on amyloid scans as a diagnostic shortcut instead of performing more comprehensive tests that include a variety of memory and logic tests. And since there is no effective treatment, a scan that suggests that a person with mild cognitive impairment actually has early Alzheimer's, may cause anxiety and be of no practical use. "What can be done with this information?" asks neurobiologist William Jagust from the University of California, Berkeley.
Some experts believe there is benefit to the scan if it helps patients and their families prepare for the expected health and lifestyle changes that accompany Alzheimer's. Others argue that the test has no meaning if it does not change the way patients are treated. The federal agency that oversees the federal health insurance, Medicare, actually supported the approach that the test is not significant in September 2013, when it refused to cover the costs of the test for now, except in certain clinical trials, because there was not enough evidence that the test improves the health of patients. Despite the disappointment, the CEO of Avid, Daniel Skobronsky, acknowledges that it will take quite a bit of time and thought to understand when it is worthwhile to use scanning, because it is such a new tool. "I think the debate is actually a good thing," he says.
The success of the clinical trial that began in December 2013 may quell the controversy. Sperling, Karlwisch and researchers at 60 medical centers in the US will scan 3,000 healthy elderly residents in an experiment to identify 1,000 people with amyloid plaques who will receive for three years a real Alzheimer's drug, called solanzumab, or alternatively a dummy drug (placebo).
However, before the first PET scans, it is necessary to scan the participants and check moods, depression and anxiety to make sure that they are able to "deal with uncertainty, and with what can be interpreted as bad news if they are informed that they have layers," says Carlwisch. "There will be people who frankly will not be allowed to participate."
With any luck, the results of the trial, which are not expected until 2018, will confirm that solanozomb may be used in a practical treatment in the future, one that will help doctors decide whether it makes sense to diagnose Alzheimer's in the early stages.
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on the notebook
Yingfei Chen is a freelance writer from Santa Cruz, California. Her articles have been published in the New York Times, Science and Smithsonian, among others.
The article was published with the permission of Scientific American Israel
