Dr. Federoff said that the analysis showed significantly lower plasma levels of serotonin, phenylalanine, proline, lysine, phosphatidylcholines (PC), taurine, and acylcarnitines (AC) in the converters. They identified 10 lipids that were depleted in the converters and not the controls. To be sure of their findings, they performed the same blood analysis on 40 others and replicated the same panel of 10 biomarkers. These biomarkers are phospholipids that play a role in the structure and function of cell membranes.
The blood markers for the 10 lipids were lower in the group that had just phenoconverted than in those who had signs of AD at the start of the study. But the levels never returned to normal, even in the AD group.
“We posit that this ten-phospholipid biomarker panel…reveals the breakdown of neural cell membranes in those individuals destined to phenoconvert from cognitive intactness to amnesic MCI or AD, and may mark the transition between preclinical states where synaptic dysfunction and early neurodegeneration give rise to subtle cognitive changes,” the scientists wrote in the Nature Medicine paper.
They said that the “accuracy for detection is equal to or greater than that obtained from most published CSF studies.”
The researchers also looked at the effects of having at least one copy of the apolipoprotein E4 (APOE4) allele and it did not seem to make a difference on the changes that they identified in the blood samples.
“It is important now to replicate our findings,” said Dr. Federoff, who said that he began this observational study to see whether they could enroll cognitively normal older people and establish a neuropsychological battery that they could use to follow people over time and identify people at the earliest signs of memory trouble.
“Our data has led to a new set of biological insights,” Dr. Federoff added. “This is an area of biology we have to probe more deeply.”
AD researchers, who were not involved with the study, said that one of the major weaknesses of the study is that the group did not have brain scans that could corroborate a pathological diagnosis of MCI or AD. “It would have been great but we just didn't have the money,” said Dr. Federoff. He is now talking to other researchers who have blood tests and brain scans on their study subjects.
The researchers are also looking at the genetic signature from the blood profiles. “This is a compelling story and it must be expanded,” said Dr. Federoff.
EXPERTS WEIGH IN
“This is an exciting finding but [it is] preliminary,” said Neil Buckholtz, PhD, director of the Division of Neurosciences at the National Institute on Aging (NIA). “We know from similar studies that something that shows up in one population may not show up in another. It needs replication.”
As for the panel identifying involvement of phospholipids, he added, “they are markers of healthy cell membranes and it makes sense that this could be part of the disease process.” He stressed that this is a long way “from a clinically useful blood test for Alzheimer's.”
Certainly, a blood test would be far less expensive than collecting cerebrospinal fluid or ordering a brain scan. “But so far the field has not had much success at finding things in blood that would predict AD,” added John Hsiao, MD, chief of the diagnosis and biomarkers for dementia program in NIA's Division of Neurosciences. “We hope it is as powerful as it seems. It tells us something about the pathology of AD and it may offer a tool to see something in the blood today that might predict symptoms years from now.”
David S. Knopman, MD, FAAN, a professor of neurology at the Mayo Clinic in Rochester, MN, and an expert on Alzheimer's biomarkers, said he believes that “the findings are overstated.” They offered no brain imaging to back up their findings, he said. “There might be some truth, but a lot more work needs to be done.” He is not so sure that what goes on in the brain doesn't stay in the brain.
Neither is Ronald C. Petersen, MD, PhD, director of the Mayo Clinic Alzheimer's Disease Research Center. Still, he said: “This [a blood test] is where we need to go. Alzheimer's is a public health issue and we need to have relatively simple non-invasive tests to see who is more likely to develop Alzheimer's. Developing a blood test for Alzheimer's is not a trivial task.”
Rima Kaddurah-Daouk, PhD, an associate professor of the pharmacometabolomics center at Duke University, sees the workings of metabolism at the very heart of every disease state. To that extent, she said, “to use these global approaches in metabolomics is a far more sophisticated way of understanding disease. It's as if you had a powerful telescope that is allowing you to see things that were not possible before.” Her work in Alzheimer's has also focused on identifying and mapping lipids.
“The beauty of this paper in Nature Medicine is that they used simple measures to identify chemistry. That allowed them to determine that there is a problem in lipid metabolism very early in the disease process, before symptoms emerge. This is a fantastic step forward. Having these tools will redefine a lot of things in the clinical field. Blood captures a lot of relevant information on pathological changes in the brain. It's no longer enough to think about the brain not being connected to the rest of the body.”
LINK UP FOR MORE INFORMATION:
•. Mapsonte M, Cheema AK, Fandaca MS, et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med
2014; E-pub 2014 Mar. 9.
© 2014 American Academy of Neurology
•. Sperling RA, et al. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association
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