UCLA researchers using innovative brain-scan technology haveshown that the abnormal brain protein deposits that define Alzheimer's diseasecan be detected in mild cognitive impairment — a condition that increases therisk for developing Alzheimer's and affects 15 to 20 million Americans. Thestudy will be published in the Dec. 21 issue of The New England Journal ofMedicine.
Scientists are in the early stages of identifying biomarkersin the blood and spinal fluid to help with Alzheimer's diagnosis, but this newstudy is the first to report a real-time "window into the brain" thatidentifies the major abnormal deposits of the disease in living people who maynot develop Alzheimer's for years to come. The researchers used positronemission tomography (PET) imaging employing a small molecule invented at UCLAthat binds to the abnormal proteins — amyloid plaquesand neurofibrillary tangles — that may cause thedisease. Previously, only an autopsy could determine the existence of thesedeposits and confirm a definitive diagnosis.
Study results found that the new method was able to trackdisease progression over a two-year period and was more effective thanconventional imaging techniques in differentiating patients with Alzheimer'sand mild cognitive impairment from normal study subjects. Researchers are now workingwith Siemens Medical to begin a clinical trial using this new molecular markerin order to obtain Food and Drug Administration approval. FDA approval wouldmake the method available in the future for use by physicians with theirpatients.
"The study suggests that we may now have a new diagnostictool for detecting pre-Alzheimer's conditions to help us identify those atrisk, perhaps years before symptoms become obvious," said Dr. Gary Small, Parlow-Solomon Professor on Aging, lead study author and aprofessor with the Semel Institute for Neuroscienceand Human Behavior at UCLA. "This imaging technology may also allow us to testnovel drug therapies and manage disease progression over time, possibly protectingthe brain before damage occurs."
The study included 83 volunteers aged 49 to 84. Based oncognitive testing, 25 patients had Alzheimer's disease, 28 had mild cognitiveimpairment and 30 were normal controls. Researchers performed PET brain scansafter intravenously injecting the volunteers with the new chemical marker,called FDDNP, which binds to the plaque and tangle deposits found inAlzheimer's patients. Scientists found distinct differences among people withnormal brain aging, people with Alzheimer's and people with mild cognitiveimpairment.
The PET imaging showed that the more advanced the disease,the higher the FDDNP concentrations in the temporal, parietal and frontal brainregions, 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 inpatients with mild cognitive impairment and advancing in those with Alzheimer'sdisease," said Dr. Jorge Barrio, a study author and professorof medical and molecular pharmacology at the David Geffen School of Medicine atUCLA.
All subjects also received a PET brain scan using a moreconventional chemical marker called FDG, which measures the metabolic functionof cells and has previously been used in aiding diagnosis for Alzheimer'sdisease. However, FDG cannot identify the abnormal brain protein deposits thatmay 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 differentiatedbetween study subject groups better than the FDG–PET combination or the MRI.
"FDDNP yielded excellent diagnostic accuracy and preciselypredicted disease progression and brain pathology accumulation," said Barrio. "FDDNP–PETalso delivers the promise of new drug monitoring in human subjects for a morerapid introduction of therapeutic candidates to control or slow progression ofthe disease."
Researchers performed follow-up scans two years later on 12research subjects, using FDDNP–PET. Patients whose conditions had grown worse —declining from normal cognitive function to mild cognitive impairment or frommild cognitive impairment to Alzheimer's disease — showed a 5 to 11 percentincrease in FDDNP binding over their previous brain scans, suggesting anincrease in plaques and tangles.
A brain autopsy completed on a follow-up Alzheimer's patientwho died 14 months later showed high plaque and tangle concentrations in areasthat had previously demonstrated high FDDNP binding values on the PET scan.
"This is the first time this pattern of plaque and tangleaccumulation has been tracked in living humans over time in a longitudinalstudy," said Small.
The study was funded by National Institutes of Health; the Department of Energy; General ClinicalResearch Centers Program; the Rotary CART Fund; the Fran and Ray Star FoundationFund for Alzheimer's Disease Research; the Ahmanson Foundation; the Larry L. Hillblom Foundation; the Lovelace Foundation; the Judith Olenick Elgart Fund for Researchon Brain Aging; the John D. French Foundation for Alzheimer's Research; and theTamkin Foundation. Department of Energy funds supportedFDDNP synthesis, which was performed at the UCLA Cyclotron Laboratory under professor Nagichettiar Satyamurthy's direction. No company provided support of anykind for this study.
Other UCLA authors include Vladimir Kepe,Ph.D.; Linda M. Ercoli, Ph.D.; PrabhaSiddarth, 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 MichaelE. Phelps, Ph.D.
UCLA owns a