Julie Price, Ph.D.

Funded in June 2004: $100,000 for 3 years

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Validating a New PET Tracer to Identify Amyloid Early in Alzheimer’s Disease

Pittsburgh researchers seek to validate a new PET imaging tracer called Pittsburgh Compound B (“PIB”) that they have developed to identify brain amyloid deposits that occur well in advance of symptomatic Alzheimer’s disease.  Thereafter, the team will modify use of the imaging tracer to create a valid and reliable version of the technique that can be used routinely in clinical studies of Alzheimer’s disease and in experimental therapies for treating it.

Related studies suggest that the hallmark build up of amyloid (a protein) in the brain in Alzheimer’s disease occurs years in advance of the onset of clinical symptoms.  Currently, validation of brain amyloid deposits occurs only at autopsy, using a dye to stain amyloid in brain tissue.  Early detection of the presence of amyloid in patients would enable researchers to determine whether symptoms worsen as amyloid increases, providing the first direct evidence of amyloid’s role in the disease’s progression.  If this is the case, as suspected, PIB could be used for early diagnosis and evaluation of the effects of treatment in depleting existing, or further preventing, amyloid deposits.

PIB is a derivative of the dye used to identify amyloid at autopsy.  Initial “Proof of Principle” that PIB could identify brain amyloid was recently published in the Annals of Neurology by Swedish collaborators, who found that PIB appears to bind to brain amyloid in living Alzheimer’s patients.  The Swedish collaborators imaged 16 Alzheimer’s patients, and found that patients’ brain areas that showed amyloid build-up with imaging corresponded to the affected areas commonly seen at autopsy.  Now, the Pittsburgh team would validate and then simplify the optimal technique for widespread research and eventual clinical use.

Two tests will be used to validate the current optimal, but complex, technique.  First, patients will undergo conventional PET imaging to determine the brain areas that show lower levels of brain activity.  These same patients then will undergo PET imaging with PIB to see if the low activity areas correspond to areas showing amyloid accumulation.  During imaging, each patient will have frequent blood samples drawn from the artery leading to the brain.  This approach provides a comparison of the amounts of PIB entering and leaving the brain.  The difference between these two measures will correspond to the amount of PIB that had bound to amyloid in the brain.

These comparisons will be made in three groups of five people each:  patients diagnosed through standard testing for Alzheimer’s disease (who should show a lot of amyloid in specific brain regions); patients with mild cognitive impairment, which is often a precursor to Alzheimer’s (who should show less amyloid); and healthy controls (who should show little or no amyloid).

If the full technique is shown to be valid and reliable, investigators then will simplify the technique to eliminate the need to draw arterial blood samples, which is a difficult and lengthy process.  After validating the simplified technique, it should be ready for widespread use in clinical research and eventually in clinical diagnosis and treatment evaluation.

Significance:  This research will validate and simplify the first available method for directly assessing brain amyloid in living people.  This tool will enable researchers to determine whether increased amyloid accumulation and its distribution in the brain are directly related to progression of dementia symptoms.  If so, PIB will become an early diagnostic tool for evaluating the effectiveness of experimental therapies designed to curtail or reverse this process early in the disease, when such therapies are most likely to be effective.

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PET Imaging of Brain Amyloid Using PIB

Our research efforts have been directed toward the development of non-invasive methods for the in vivo measurement of amyloid plaques. Our group recently collaborated with researchers in Uppsala, Sweden, to perform the first human positron emission tomography (PET) studies of a new amyloid-binding radiotracer, named PIB (Pittsburgh Compound B). These first "proof-of-concept" human studies demonstrated high PIB retention in AD subjects (n=16) in brain areas known to have high amyloid levels in AD relative to controls (n=9). The next steps in our efforts are to 1) optimize and validate the PIB PET methodology using fully quantitative pharmacokinetic modeling techniques (using arterial blood) and 2) compare this optimized method to simpler modeling techniques (not requiring blood sampling) that can be easily transferred into routine use for larger scale, multi-center research studies and, potentially, for clinical studies.

PIB PET studies will be acquired in 3 subject groups: mild-to-moderate AD dementia (n=5), mild cognitive impairment (n=5), and elderly controls (n=5). Fully quantitative and simpler pharmacokinetic models will be iteratively applied to the data to identify the optimal fully quantitative technique and the most valid and reliable simpler technique. To put the new PIB PET findings into the context of existing functional neuroimaging data, PIB localization will be related to measures of brain glucose metabolism by comparing anatomically standardized maps of amyloid binding to maps of cerebral metabolism (using [18F]FDG)—a technique that has been extensively used as a metabolic index in AD.

The central goal of this application is the identification of a simple PIB PET method that can be routinely applied and has been rigorously validated based upon the optimized fully quantitative method.

Hypothesis:
A simple and valid method can be identified for routine imaging of amyloid deposition in living humans using positron emission tomography (PET) and the amyloid-imaging agent, Pittsburgh Compound-B (PIB), through systematic evaluation of fully quantitative studies

Goals:
1.  To acquire and evaluate fully quantitative PIB PET data throughout the brain in 5 mild-moderate AD patients, 5 subjects with mild cognitive impairment (MCI), and 5 cognitively normal control subjects.
2.  To identify a valid, simple and reliable PET quantitation method for the routine measure of amyloid retention in vivo.
3.  To compare PIB retention to glucose metabolism determined by FDG PET studies in the same 5 mild-moderate AD patients, 5 subjects with MCI, and 5 cognitively normal control subjects

Methods:
All subjects will be recruited after evaluation at the University of Pittsburgh Alzheimer's Disease Research Center. A magnetic resonance imaging (MRI) scan will be obtained for each subject for anatomical localization of regions-of-interest and to correct for cerebral atrophy.  Dynamic PIB and FDG imaging studies will be performed with arterial blood sampling. Fully dynamic PIB PET data will be acquired to allow flexibility for subsequent analysis by multiple approaches that vary in complexity, accuracy, and reliability (e.g., compartmental modeling, graphical analyses, and statistical parametric methods).

Quantitative PIB PET studies showed that it was valid to use simpler semi-quantitative methods, as all yielded higher PIB retention (amyloid load) for AD subjects than for controls with strongest differences (p<0.001) in posterior cingulate, frontal, and parietal cortices.  Analyses of PIB and FDG data collected on the same day in 10 mild AD and 11 control subjects showed greater distinction of AD and control subjects by the cortical PIB PET measures (p<1E-10) than by the FDG measures of metabolism (p<0.1), for this small sample.

Butters M.A., Klunk W.E., Mathis C.A., Price J.C., Ziolko S.K., Hoge J.A., Tsopelas N.D., Lopresti B.J., Reynolds C.F. III, DeKosky S.T., and Meltzer C.C. Imaging Alzheimer pathology in late-life depression with PET and Pittsburgh Compound-B.  Alzheimer Dis Assoc Disord. 2008 Jul-Sep;22(3):261-8.

Raji C.A., Becker J.T., Tsopelas N.D., Price J.C., Mathis C.A., Saxton J.A., Lopresti B.J., Hoge J.A., Ziolko S.K., DeKosky S.T., and Klunk W.E. Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer’s disease with Pittsburgh Compound B. J Neurosci Methods. 2008 Jul 30;172(2):277-82.

Ikonomovic M.D., Klunk W.E., Abrahamson E.E., Mathis C.A., Price J.C., Tsopelas N.D., Lopresti B.J., Ziolko S.K., Bi W., Paljug W.R., Debnath M.L., Hope C.E., Isanski B.A., Hamilton R.L. and DeKosky S.T. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain. 2008 Jun;131(Pt 6):1630-45.

Klunk W.E., Price J.C., Mathis C.A., Tsopelas N.D., Lopresti B.J., Ziolko S.K., Bi W., Hoge J.A., Ikonomovic M.D., Saxton J.A., Snitz B.E., Pollen D.A., Moonis M., Lippa C.F., Swearer J.M., Johnson K.A., Rentz D.M., Fischman A.J., Aizenstein H.J., and DeKosky S.T.. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84.

Ziolko S.K., Weissfeld L.A., Klunk W.E., Mathis C.A., Hoge J.A., Lopresti B.J., DeKosky S.T., and Price J.C.  Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease.  Neuroimage. 2006 Oct 15;33(1):94-102.