In Vivo Amyloid Measures in Mild Cognitive Impairment: 3-Site Stability Study

Chester A. Mathis, Ph.D.

University of Pittsburgh , Pittsburgh, PA

Grant Program:

Clinical Neuroscience Research

Funded in:

September 2004, for 3 years

Funding Amount:


Lay Summary

New Imaging Technique's Capacity for Assessing Treatments in Alzheimer's Disease

Investigators from the three institutions will undertake a three-step study to determine whether PET-PIB imaging can reliably detect the presence and distribution of brain amyloid in people. Researchers at each institution will enroll five cognitively normal “control” participants and ten mild cognitive impairment (MCI) individuals. First, the collaborating researchers will use PET-PIB imaging to develop baseline information on the presence and extent of brain amyloid deposits in patients with MCI, a significant percentage of whom would be expected to develop Alzheimer’s disease within a few years. This would be compared to baseline levels for the control participants, who are anticipated to have little or no brain amyloid. To do this, the investigators will image the MCI and control participants initially to establish the baseline findings of whether amyloid is present in the brain and, if so, where and in what amounts. The researchers then will re-image the same participants within three weeks to assure the stability of the imaging results.

Next, the collaborators will re-image the participants at one year to observe any increases in amyloid deposits and to determine whether any MCI individuals who initially showed no amyloid now had evidence of its presence. This one-year time interval was chosen because most clinical studies of experimental therapies are designed to identify changes within a year from baseline.

Through this three-stage study, the collaborating investigators will test four hypotheses. First, differences in PIB retention seen in control and MCI participants will be statistically equivalent at each of the three sites. Second, there will be only a small variation (no more than five to ten percent) between the initial and three-week baseline imaging of amyloid. Third, approximately one-half of MCI individuals will show evidence of brain amyloid deposition. Fourth, PIB retention (and indication that PIB has bound to amyloid) will not increase in the cognitively healthy control participants, but will show a significant increase in MCI individuals at one year.

If this collaborative study demonstrates that PET-PIB imaging provides a reliable and valid multi-site determination of changes in amyloid deposition within a one-year time frame, the investigators anticipate that pharmaceutical companies and the federal Food and Drug Administration, which regulates the approval of new drugs and biologics, will recognize that PET-PIB imaging can provide a “surrogate” marker of the effects of various experimental treatments designed to reduce or prevent amyloid accumulation. In other words, pharmaceutical companies would be able to determine whether experimental therapies that target amyloid production or metabolism reduce brain amyloid or prevented its additional accumulation, providing a surrogate measure of therapeutic efficacy.


In Vivo Amyloid Measures in MCI: 3-Site Stability Study

The ability to accurately quantify amyloid deposition in the living brain has several important implications for the diagnosis and treatment of Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). Our group has recently reported the first human study with a new PET tracer known as Pittsburgh Compound-B (PIB). PIB localized in brain regions known to have extensive amyloid deposition (e.g. frontal, temporal and parietal cortex) and did not accumulate in brain regions known to be relatively free of neuritic plaques (e.g. cerebellum). While the diagnostic implications are important, of greater immediate interest is the use of this amyloid imaging technology to hasten the development of effective anti-amyloid therapies. The ability to monitor amyloid load before and after treatment would greatly enhance our ability to evaluate the effectiveness of these anti-amyloid therapies.

Patients with MCI are a particularly attractive target group for therapy. This apparently prodromal phase of AD is of particular interest because it presents a mild form of the clinical symptoms of AD and a target for early intervention. Typical drug trials will involve multiple sites and comparison of pre- and post-treatment states after six months to one year. If amyloid imaging is to be used as one surrogate endpoint in these trials, then a baseline of untreated patients is necessary in order to plan the trials and interpret the results. Providing this baseline data is the major motivation for this project. This project is characterized by four key elements. First, amyloid imaging studies will be performed on MCI subjects evaluated by experienced ADRC clinicians. Second, a short-term test/re-test will be performed to assure the stability of the test itself. Third, a one-year follow-up study will be performed to determine the expected degree of change in amyloid load in MCI patients over one year. Fourth, the study will be done at three sites (University of Pittsburgh, Washington University, and University of Michigan) to simulate a multi-site drug trial. This multi-site design is critical for providing the type of information necessary for pharmaceutical companies to determine the feasibility of adding amyloid imaging components to several sites of a multi-site drug trial. We propose to study 5 cognitively normal control subjects and 10 MCI-amnestic patients at each of the 3 sites at baseline (test and re-test studies) and one year later. We will leverage the expertise of existing Alzheimer Disease Research Centers at each site to provide carefully evaluated MCI-amnestic patients and controls. The results of this multi-site PIB imaging collaboration will provide us with quantitative information that will allow us to better understand to what extent one can expect to see significant effects of anti-amyloid therapies in MCI-amnestic patients over one year (a time period typical of AD therapeutic trials).

Investigator Biographies

Chester A. Mathis, Ph.D.

Chester A. Mathis, Ph.D., is Professor of Radiology, Pharmaceutical Sciences, and Pharmacology at the University of Pittsburgh School of Medicine. He is also Senior Chemist and Director of the University of Pittsburgh Positron Emission Tomography (PET) Facility. Dr. Mathis received a Ph.D. in chemistry from the University of California, Davis in 1979. He conducted postdoctoral research at UC Davis and UC Berkeley in the laboratories of Kenneth Krohn and Thomas Budinger, where he applied radiotracer methods to study biological and medical problems. He was a staff chemist at Lawrence Berkeley National Laboratory from 1984 to 1992, where he worked on the development of radiopharmaceuticals for a variety of PET imaging applications. He joined the faculty of the University of Pittsburgh School of Medicine in 1992.

Dr. Mathis has a long standing interest in applying synthetic radiochemistry techniques to develop PET radiopharmaceuticals to study brain function

in vivo. Over the past 20 years, Dr. Mathis focused primarily on the development of radiotracers to image the serotonin and dopamine neuroreceptor systems, as well as agents to evaluate other aspects of normal and abnormal function in the central nervous system using PET imaging techniques. Approximately 10 years ago, Dr. Mathis joined efforts with Dr. William E. Klunk of the Department of Psychiatry at the University of Pittsburgh to devise a PET radiotracer capable of imaging amyloid. This work led to the development of a new class of radiopharmaceutical agents, among which is Pittsburgh Compound-B, to non-invasively assess amyloid load in the living human brain using PET imaging methodology.

Selected Publications

Mintun M.A., Larossa G.N., Sheline Y.I., Dence C.S., Lee S.Y., Mach R.H., Klunk W.E., Mathis C.A., DeKosky S.T., and Morris J.C.   [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease.  Neurology. 2006 Aug 8;67(3):446-52.