One of the hallmarks of Alzheimer's is the accumulation of beta-amyloid plaques in the brain, but what part those plaques play in the development of the disease isn't clear.
Now researchers have taken the first steps to trace the progression of plaque buildup in living patients. This way of "staging" the disease has implications for research and one day may help doctors treat this debilitating, fatal disease.
"It is possible to stage individuals in terms of how advanced their beta-amyloid deposition is, using PET scans," said lead researcher Dr. Niklas Mattsson, an associate professor of clinical neuroscience at Lund University in Sweden.
When beta-amyloid appears, it follows certain stages, he explained. Some brain regions are involved early, others at the intermediate stage, and some in the late stage of Alzheimer's.
"These stages are also associated with other hallmarks of Alzheimer's disease, such as levels of tau [another type of protein] in cerebral spinal fluid, cognitive decline and the wasting away of brain cells," Mattsson added.
"This staging system can be used both to improve research and perhaps also in clinical trials, to see if certain drugs are likely to be most effective in certain stages of Alzheimer's," Mattsson said.
By the time Alzheimer's is typically diagnosed, the brain is already destroyed, said Meredith Braskie, an assistant professor of neurology at the University of Southern California in Los Angeles. She was not involved with the study.
The disease takes years to develop, which is why finding a way to diagnose it early is important, Braskie said. Most studies on plaque have been done on the brains of dead people.
"This study is important because they were looking at how amyloid spreads in living patients and coming up with stages for that," Braskie said.
Although no cure exists for Alzheimer's today, this finding could also help in testing drugs as they are developed, she said.
But, "this isn't directly related to patient care," Braskie said. "It's more for research to see if treatments are working."
For the study, Mattsson and his colleagues used PET scans from the Alzheimer's Disease Neuroimaging Initiative database. Among the 741 participants, 304 had no cognitive impairment, 384 had mild cognitive impairment, and 53 had Alzheimer's disease. Patients were followed up at two, four and six years.
At the start of the study, about 98% of the 2,072 scans weren't staged. Of those in the earliest stage of plaque development, about 15% would likely progress to a more advanced stage, as would 71% of those at stage 1 and 53% of those at stage 2.
As patients moved from stage 1 to stages 2 and 3, amyloid plaque developed in more vital areas of the brain, the researchers noted.
Interestingly, nearly 1% of the patients reverted to a lower stage, the researchers found. Higher stages were linked to higher concentrations of tau in cerebral spinal fluid. More tau in stage 2 indicated a more rapid progression to cognitive decline. The researchers were able to confirm their findings in a different group of 474 patients.
The areas affected in the brain differed in each stage and were also linked to differences in genetics, blood circulation, brain cell behavior and cholesterol levels.
"I think that it is clear from these data that the earlier the diagnosis of Alzheimer's is supported by amyloid imaging, the earlier clinicians are likely to initiate drug therapy," said Dr. Sam Gandy. He's chair of Alzheimer's Disease Research and director of the Mount Sinai Center for Cognitive Health and NFL Neurological Care in New York City.
This would be a change from current practice, which is not to start drug therapy until patients have advanced beyond the mild cognitive impairment and are well into mild Alzheimer's disease, said Gandy, who had no part in the study.
However, Gandy isn't sure that beginning drug therapy when mild cognitive impairment starts and a scan shows plaque would benefit all or only some patients.
Also, he would like to see if the staging system would work the same way among patients with and without the APOE gene mutations, which are linked to Alzhe...
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