While imagers and primary-care physicians have for years been able to point out the clinical and metabolic signs that signal Alzheimer's, a new PET agent highlights the source of the disease -- amylotic plaques themselves.
2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2naphthyl}ethylidene)malononitrile, known more simply as [F-18]FDDNP, was developed at the University of California, Los Angeles. It binds to the neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) characteristic of the neurodegenerative disease.
"We were working several years ago on fluorescent molecules, paying special attention to their viscosity and polarity properties. I theorized that these molecules would make good markers for APs. Once we demonstrated FDDNP's properties to detect plaques with autopsy samples and other in vitro tests, the logical next step was to study it in living humans," said Dr. Jorge R. Barrio, a professor of molecular and medical pharmacology at UCLA.
In a study published in the January American Journal of Geriatric Psychiatry, researchers found that the agent could localize in the brains of living Alzheimer's patients NFTs and APs that were previously confirmed only at autopsy.
FDG-PET and [F-18]FDDNP could be used in conjunction to diagnose Alzheimer's disease, according to Barrio. Because FDG-PET looks at neuron death and shows metabolic deficits associated with AD, it could be used to validate the early diagnosis made by FDDNP.
"Ideally, you'd like to diagnose AD as early as possible," he said. "We plan on using this tracer to image at-risk patients, those with the AD gene marker and those with a strong family history of AD. The question of exactly when to use FDDNP is for future studies."
The initial study included nine subjects ages 62 to 85, seven with probable and two with possible Alzheimer's disease. Seven control subjects were recruited from an existing subject pool without regard to family history of AD. All subjects received neurological, psychiatric, and neuropsychological evaluation, including an FDG-PET scan to assess regional brain glucose metabolism. Researchers performed venous catherization and then administered FDDNP as a bolus injection. Immediately after FDDNP administration, they obtained sequential emission scans.
The study concluded that FDDNP crosses the blood-brain barrier in proportion to blood flow and can bind itself to APs and NFTs in the living human brain. Researchers found that [F-18]FDDNP accumulated in brain areas with the low glucose metabolism characteristic of the presence of APs and NFTs. It also tends to linger in those regions longer than in areas with limited neuropathic lesions. Patients in the Alzheimer's cohort showed significantly higher uptake of the tracer compared with the control group.
One caveat, however, is some concern about the effect of blood flow on relative residence time (RRT) values.
"With significant damage in the brain, as occurs with Alzheimer's lesions, blood flow has been shown to be impaired. As indicated in the paper, these FDDNP results may be affected by blood flow, but we are working on untangling the results from those factors," said Barrio.
By Merlina Trevino
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Merlina Trevino
