Imaging Method Detects Alzheimer's Risk

An innovative brain-scan technology shows promise in detecting those at risk for developing Alzheimer's disease, years before symptoms become obvious, by showing in living brains the abnormal protein deposits that can lead to the disease -- something that previously could only be confirmed by autopsy.

Scientists at the University of California, Los Angeles are in the early stages of identifying biomarkers in the blood and spinal fluid to help with Alzheimer's diagnosis, but they said this study is the first to report a real-time "window into the brain" that identifies the major abnormal deposits of the disease, which affects 15 to 20 million Americans, in living people who may not develop it for years to come.

Brain PET scans from a healthy volunteer (left), a subject with mild cognitive impairment (middle) and a subject with Alzheimer's disease (right). Red and yellow areas show the new chemical marker FDDNP binding to abnormal brain proteins or "plaques and tangles." (Images: UCLA)

The researchers used positron emission tomography (PET) imaging employing a small molecule invented at UCLA that binds to the abnormal proteins -- amyloid plaques and neurofibrillary tangles -- that may cause the disease. Previously, only an autopsy could determine the existence of these deposits and confirm a definitive diagnosis.

Study results found that the new method was able to track disease progression over a two-year period and was more effective than conventional imaging techniques in differentiating patients with Alzheimer's and mild cognitive impairment from normal study subjects. Mild cognitive impairment is a condition that increases the risk for developing Alzheimer's.

"The study suggests that we may now have a new diagnostic tool for detecting pre-Alzheimer's conditions to help us identify those at risk, perhaps years before symptoms become obvious," said Gary Small, Parlow-Solomon Professor on Aging, lead study author and a professor with the Semel Institute for Neuroscience and Human Behavior at UCLA. "This imaging technology may also allow us to test novel drug therapies and manage disease progression over time, possibly protecting the brain before damage occurs."

The study included 83 volunteers aged 49 to 84. Based on cognitive testing, 25 patients had Alzheimer's disease, 28 had mild cognitive impairment and 30 were normal controls. Researchers performed PET brain scans after intravenously injecting the volunteers with the new chemical marker, called FDDNP, which binds to the plaque and tangle deposits found in Alzheimer's patients. Scientists found distinct differences among people with normal brain aging, people with Alzheimer's and people with mild cognitive impairment.

The PET imaging showed that the more advanced the disease, the higher the FDDNP concentrations in the temporal, parietal and frontal brain regions, where the abnormal protein deposits typically accumulate. Patients with Alzheimer's showed the most FDDNP binding, indicating a higher level of plaques and tangles than other subjects.

"We could see the definitive patterns starting early in patients with mild cognitive impairment and advancing in those with Alzheimer's disease," said Jorge Barrio, a study author and professor of medical and molecular pharmacology at UCLA's David Geffen School of Medicine.

All subjects also received a PET brain scan using a more conventional chemical marker called FDG, which measures the metabolic function of cells and has previously been used in aiding diagnosis for Alzheimer's disease. However, FDG cannot identify the abnormal brain protein deposits that may cause the disease. In addition, 72 subjects received magnetic resonance imaging (MRI) scans, which show brain structure and size.

Scientists found that the FDDNP–PET scan combination differentiated between study subject groups better than the FDG–PET combination or the MRI.

"FDDNP yielded excellent diagnostic accuracy and precisely predicted disease progression and brain pathology accumulation," said Barrio. "FDDNP–PET also delivers the promise of new drug monitoring in human subjects for a more rapid introduction of therapeutic candidates to control or slow progression of the disease."

Researchers performed follow-up scans two years later on 12 research subjects, using FDDNP–PET. Patients whose conditions had grown worse -- declining from normal cognitive function to mild cognitive impairment or from mild cognitive impairment to Alzheimer's disease -- showed a 5 to 11 percent increase in FDDNP binding over their previous brain scans, suggesting an increase in plaques and tangles.

A brain autopsy completed on a follow-up Alzheimer's patient who died 14 months later showed high plaque and tangle concentrations in areas that had previously demonstrated high FDDNP binding values on the PET scan. "This is the first time this pattern of plaque and tangle accumulation has been tracked in living humans over time in a longitudinal study," said Small.

The study was published in the Dec. 21 issue of The New England Journal of Medicine. It was funded by National Institutes of Health,the Department of Energy, General Clinical Research Centers Program and numerous foundations. The DoE funds supported FDDNP synthesis, which was performed at the UCLA Cyclotron Laboratory.

UCLA researchers are now working with Siemens Medical to begin a clinical trial using the new molecular marker to obtain Food and Drug Administration approval. UCLA owns a patent on the approach and has licensed it to Siemens.

For more information, visit: www.ucla.edu