PET Brain Imaging in Alzheimer's Disease for Early Detection and Treatment

Gary W. Small, M.D

UCLA Neuropsychiatric Institute

Funded in December, 1999: $100000 for 1 years
LAY SUMMARY . BIOGRAPHY . HYPOTHESIS . FINDINGS . SELECTED PUBLICATIONS .

INVESTIGATOR BIOGRAPHIES

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Gary W. Small, M.D

Parlow-Solomon Professor on Aging, Professor of Psychiatry and Biobehavioral Sciences
UCLA Neuropsychiatric Institute

HYPOTHESIS

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Hypothesis:
1. To determine whether PET imaging, using a newly synthesized, radiolabeled fluorinated probe, will differentiate patients with AD from those with MCI and from cognitive intact controls.

2. PET imaging shows highest FDDNP concentrations in Alzheimer's Disease (AD) affected brain regions in AD patients, intermediate concentrations in mild cognitive impairment (MCI; subjects with impaired delayed recall), and lowest in age-matched controls without cognitive decline.

3. FDDNP-PET and FDG-PET imaging patterns are inversely correlated.

Goals:
Autopsy studies of the brains of AD patients show characteristic brain cell damage lesions known as neuritic plaques (NPs) and neurofibrillary tangles (NFTs). Currently these very small lesions can only be seen at autopsy under microscope.  No one yet has been able to visualize them in a living human. This project introduces an innovative means to accomplish this goal. Improving diagnostic accuracy early in the course of AD will increase the accuracy of assessing the effectiveness of new therapies and facilitate early treatment initiation in the preclinical stages.

Methods:
Subject Recruitment: Researchers will screen and evaluate volunteers in order to recruit and diagnose three age and sex matched subject groups: patients with probable AD, patients with MCI, and cognitively intact controls. Following initial screening, standard diagnostic procedures will be used, including neuropsychological testing to ensure subjects meet criteria for MCI. Data from a total of 30 subjects (10 from each group) will be available.

Brain Imaging Procedures: For each subject enrolled, researchers will perform two PET scans (FDDNP and FDG) and a MRI scan. They will then determine regions of interest on the MRI scans and register them to the PET scans for analysis of regional cerebral glucose metabolism and FDDNP accumulation.

Genetic Imaging Measure: Blood samples will be drawn and DNA isolated from each subject in order to determine APOE genotypes.

Follow-on Funding: Ahmanson Foundation, Judith Olenick Elgart Fund for Research on Brain Aging, Institute for the Study of Aging, and a Program Project Grant from the National Institute on Aging.

 

FINDINGS

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A total of 83 volunteers with memory complaints who had neurologic and psychiatric evaluations were studied.  Cognitive testing classified 25 subjects as having AD, 28 as having MCI, and 30 as normal controls.  PET scanning was performed after intravenous injections of FDDNP.  All subjects also received FDG-PET scans, and 72 received magnetic resonance imaging (MRI) scans.  We found that global FDDNP-PET binding (temporal, parietal, posterior cingulate, and frontal average) was lower for the control group compared with the MCI group (p<0.001), which showed lower binding than the AD group (p<0.001).  Higher global FDDNP binding values correlated with lower FDG-PET values in posterior cingulate (Spearman correlation coefficient rs = -0.64, p<0.001) and parietal (rs = -0.62, p<0.001) regions.  Higher global FDDNP binding values correlated significantly with lower MRI medial temporal volumes (rs = -0.28, p=0.02) and greater MRI ventricular volumes (rs = 0.36, p=0.002).  Of these subjects receiving baseline assessments, 12 were available for follow-up evaluation approximately two years later.  Overall, subjects who progressed clinically showed increased FDDNP binding (5 to 11 percent).  Moreover, autopsy (14 months after FDDNP-PET scanning) follow-up of an AD patient demonstrated high plaque and tangle concentrations in brain regions with high FDDNP binding.

Studies are now being started to use FDDNP-PET to monitor treatment interventions.  In addition, UCLA has licensed this technology to industry in order to pursue FDA approval.

 

SELECTED PUBLICATIONS

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Small G.W., Kepe V., Ercoli L., Siddarth P., Miller K., Bookheimer S.Y., Lavretsky H., Burggren A.C., Cole G., Vinters H.V., Thompson P.M., Huang S-C, Satyamurthy N., Phelps M.E., and Barrio J.R.  PET of brain amyloid and tau in mild cognitive impairment.  N Engl J Med. 2006 Dec 21;355(25):2652-63.

Shoghi-Jadid K., Small G.W., Agdeppa E.D., Kepe V., Ercoli L.M., Siddarth P., Read S., Satyamurthy N., Petric A., Huang S.C., and Barrio J.R. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease.  Am J Geriatr Psychiatry. 2002 Jan-Feb;10(1):24-35.

Agdeppa E.D., Kepe V., Shoghi-Jadid K., Satyamurthy N., Small G.W., Petric A., Vinters H.V., Huang S.C., and Barrio J.R. In vivo and in vitro labeling of plaques and tangles in the brain of an Alzheimer's disease patient: A case study. Journal of Nuclear Medicine, 42:65P (No. 242).

Agdeppa E.D., Kepe V., Flores-Torres S., Liu J., Satyamurthy N., Petric A., Small G.W., Huang S.C., Barrio J.R. (2001). In vitro binding characteristics of FDDNP and a new analog for synthetic ?-Amyloid fibrils. Journal of Nuclear Medicine, 42:64-65P (No. 241).