UCLA researchers using innovative brain-scan technology have shown that the abnormal brain protein deposits that define Alzheimer's disease can be detected in mild cognitive impairment — a condition that increases the risk for developing Alzheimer's and affects 15 to 20 million Americans. The study is published in the Dec. 21 issue of The New England Journal of Medicine.

Scientists are in the early stages of identifying biomarkers in the blood and spinal fluid to help with Alzheimer's diagnosis, but this new study is the first to report a real-time "window into the brain" that identifies the major abnormal deposits of the disease in living people who may not develop Alzheimer's for years to come. 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. Researchers are now working with Siemens Medical to begin a clinical trial using this new molecular marker in order to obtain Food and Drug Administration approval. FDA approval would make the method available in the future for use by physicians with their patients.

"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 Dr. 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 Dr. Jorge Barrio, a study author and professor of medical and molecular pharmacology at the David Geffen School of Medicine at UCLA.

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 funded by National Institutes of Health; the Department of Energy; General Clinical Research Centers Program; the Rotary CART Fund; the Fran and Ray Star Foundation Fund for Alzheimer's Disease Research; the Ahmanson Foundation; the Larry L. Hillblom Foundation; the Lovelace Foundation; the Judith Olenick Elgart Fund for Research on Brain Aging; the John D. French Foundation for Alzheimer's Research; and the Tamkin Foundation. Department of Energy funds supported FDDNP synthesis, which was performed at the UCLA Cyclotron Laboratory under professor Nagichettiar Satyamurthy's direction. No company provided support of any kind for this study.

Other UCLA authors include Vladimir Kepe, Ph.D.; Linda M. Ercoli, Ph.D.; Prabha Siddarth, Ph.D.; Susan Y. Bookheimer, Ph.D.; Karen J. Miller, Ph.D.; Dr. Helen Lavretsky; Alison C. Burggren, Ph.D.; Greg M.Cole, Ph.D.; Dr. Harry V. Vinters; Paul M. Thompson, Ph.D.; S. C. Huang, Ph.D.; N.Satyamurthy, Ph.D.; and Michael E. Phelps, Ph.D.


For more information, go to
http://www.nih.gov/news/pr/dec2006/nia-20.htm