PET Amyloid Imaging in Nondemented Elderly to Evaluate Alzheimer Risk

John Morris, M.D.

Washington University School of Medicine

Funded in June, 2004: $100000 for 3 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . FINDINGS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Using a New PET Amyloid Imaging Technique to Evaluate Alzheimer’s Risk

Three studies would be undertaken to test the hypothesis that brain uptake of the new PET imaging tracer called PIB, by binding to a protein called amyloid, identifies the preclinical (asymptomatic) phase of Alzheimer’s disease.  If the hypothesis is correct, PTB PET imaging could be used to diagnose the disease early and to assess the effects of treatment.

By the time Alzheimer’s symptoms occur, 60 percent of brain cells have been lost.  Early diagnosis might enable effective treatment before so many brain cells are lost through the disease.  Pittsburgh Compound B (PIB), developed by University of Pittsburgh researchers, is a radio-tracer that appears to detect amyloid, the protein that builds up in the brains of Alzheimer’s disease patients.  The Washington University investigators will embark on three studies to assess the ability of PET-PIB imaging to identify amyloid before Alzheimer’s symptoms occur.

First, the investigators will replicate the Pittsburgh group’s preliminary findings that brain retention of PIB differentiates people with Alzheimer’s disease from healthy (non-demented) older people.  The Washington University researchers also will confirm that quantitative methods for assessing PIB’s potential to bind to amyloid provide an accurate measure of PIB uptake.

Next, the investigators will determine how prevalent it is for older people to have asymptomatic accumulation of amyloid as detected by PIB.  This study will provide an estimate of the percent of older non-demented people who, nonetheless, are in the early stages of the disease.  The researchers will see whether this rate corresponds to the degree to which amyloid deposits are found at autopsy in no-demented, elderly people who have died.  Third, the investigators will follow all adults being studied to determine what percent do not develop symptoms but have amyloid accumulation.  Investigators will further determine the percent of adults who appear to have no amyloid accumulation but, nevertheless, develop dementia symptoms.  This analysis will help to determine how accurate PIB-PET is, by determining the number of people falsely diagnosed as having Alzheimer’s, and the number who have early (asymptomatic) Alzheimer’s that is not detected by PIB-PET. 

Significance:  If these studies demonstrate that PET imaging with PIB accurately identifies the preclinical phase of Alzheimer’s disease, they will lead to large-scale investigations to determine the role of amyloid imaging in detecting, diagnosing, treating, and potentially preventing Alzheimer’s disease.

ABSTRACT

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PET Amyloid Imaging in Nondemented Elderly to Evaluate Alzheimer Risk

We propose that Alzheimer's disease (AD) has a preclinical stage lasting years or even decades in which cerebral deposits of the peptide amyloid-β gradually accumulate in the absence of symptoms until sufficient brain damage eventually occurs to allow dementia to be expressed. Novel anti-amyloid therapeutic strategies to possibly prevent the development of clinical AD are now coming into clinical trial. It is imperative that nondemented individuals in the preclinical stage of AD, who are at very high risk for developing dementia, be identified, as it may be these individuals who will optimally benefit from potential disease modifying interventions. Now imaging detection of cerebral amlyoid deposit in nondemented individual not only is feasible, but it may help detect the preclinical stage of AD that, unless prevented, eventually will result in dementia.

Using positron emission tomography and a new tracer, [11C] benzothiazole-aniline or Pittsburg Compound-B (PIB), human brain deposits of amyloid will be imaged in a sample of nondemented of elderly subjects. The main hypothesis is that brain uptake of the tracer identifies the preclinical phase of AD.

Three specific aims will evaluate aspects of this hypothesis:

1. To replicate the initial report that cerebral retention of PIB, measured qualitatively by standardized uptake value, distinguishes AD subjects from nondemented control individuals and that quantitative methods (e.g., PIB binding potential) provide an accurate measure of PIB uptake;

2. To determine the prevalence of nondemented older individuals with abnormal PIB retention as a putative antecedent biomarker for AD; and

3. To assess the rate of subsequent development of symptomatic AD in nondemented individuals with abnormal PIB retention in comparison with the rate of dementia for those without abnormal PIB retention.

HYPOTHESIS

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Hypothesis:
We propose that Alzheimer's disease (AD) has a preclinical stage lasting years or even decades in which cerebral deposits of the peptide amyloid-beta gradually accumulate in the absence of symptoms until sufficient brain damage eventually occurs to allow dementia to be expressed.  Using positron emission tomography and a new tracer, [11C] benzothiazole-aniline, or Pittsburgh Compund-B (PIB),, human brain deposits of amyloid will be imaged in a sample of nondemented elderly subjects.  The main hypothesis is that brain uptake of the tracer identifies the preclinical phase of AD.

Goals:
1. To replicate the initial report by WE Klunk and colleagues that cerebral retention of PIB, measured qualitatively by standardized uptake value, distinguishes AD subjects from nondemented control individuals and that quantitative methods (e.g., PIB binding potential) provide an accurate measure of PIB uptake.

2. To determine whether abnormal PIB retention in nondemented older individuals serves as an antecedent biomarker for AD.

3. To assess the rate of subsequent development of symptomatic AD in nondemented individuals with abnormal PIB retention in comparison with the rate of dementia for those without abnormal PIB retention.

Methods:
We will test the utility of PIB as detected by PET in labeling amyloid deposits in nondemented older subjects.  This study will implement and test a novel PET tracer that binds in vivo to human amyloid plaques. The radiosynthesis and animal characterization of the PIB tracer, a [11C]benzothiazole-aniline, has been developed at theUniversity of Pittsburgh.  We are collaborating with the developers, Dr William Klunk and Dr Chet Mathis, and have their encouragement to conduct the proposed studies at Washington University with their compound.

Subjects (n=25) between the ages of 75 and 90 will be recruited from the  Clinical Core of the Alzheimer’s Disease Research Center (ADRC).  All subjects are assessed annually.  Dementia severity is staged by the Clinical Dementia Rating (CDR), where CDR 0 represents no dementia and CDR 0.5 and CDR 1 represents very mild and mild dementia, respectively.

To address specific aim 1, five CDR 0.5 DAT subjects and five CDR 0 nondemented subjects will be studied to evaluate the potential for PIB to discriminate the earliest symptomatic stage of AD (i.e., CDR 0.5) from nondemented aging. 

An additional 15 CDR 0 subjects will be studied to address specific aims 2 and 3:  the prevalence of PIB retention in nondemented elderly and how it relates to rate of developing dementia.  In addition to the PET amyloid imaging procedure, all subjects will receive full clinical assessment, psychometric testing, and apolipoprotein E genotype, and magnetic resonance imaging (MRI).  Annual clinical and cognitive assessments though the Clinical Core will determine which subjects develop dementia (specific aim 3), defined as a CDR score = 0.5.

FINDINGS

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Lay Results:
Although there are no known cures for Alzheimer’s disease (AD) or treatments to prevent AD, scientists have made great progress in understanding this condition.  For example, they know that a protein called amyloid is present in the brains of people with AD.  The researchers of this study believe that amyloid deposits occur years, or even decades, before symptoms of AD occur (such as a decline in memory and thinking abilities).  With the use of a radioactive tracer called Pittsburgh Compound-B (PIB) that binds to amyloid in the brain and with positron emission tomography (PET) scans, we have been able to identify individuals that have a high level of PIB but no dementia.  We found that the brains of these individuals look the same as those who do have dementia of the Alzheimer’s type (DAT).  We have also conducted tests of thinking and memory on the nondemented/high PIB individuals.  Their performance was not as good as those who are nondemented with low PIB.  We are considering the possibility that high PIB might be associated with subtle, but early, changes in one’s thinking and memory.  Although it is too early to determine whether those with no dementia but high PIB will develop AD over time (and how quickly this happens), our results show that it may be possible to detect AD even before symptoms of AD occur.  If scientists and physicians are able to diagnose AD at an earlier stage, then the possibility of treatments to improve quality of life for AD patients will be greatly increased.

Scientific Results:
As of June 30, 2007, 77 subjects were studied with PIB PET (mean age 76.4 years ± 8.6 years).  26 of these subjects were very mildly or mildly demented, with a Clinical Dementia Rating of 0.5 or 1.0, respectively.  This data replicates Klunk et al. (2004) by showing much higher PIB binding in the demented group compared with the nondemented group (Aim 1).  Our results also show that a subset of nondemented elderly subjects have elevated PIB levels indicating the likely presence of preclinical AD. A preliminary description of this has been published (Mintun et al., 2006) and this has also been seen when comparing the PIB results to Aβ CSF levels (Fagan et al., 2006).  We have also been able to quantitate, as described by PIB binding potentials (BPs), the density of PIB binding sites using the Logan graph analysis and the cerebral cortex for the reference tissue (Aim 1).  Nondemented subjects with elevated cortical BP values were not significantly different from the DAT subjects’ BP values (Mintun et al., 2006).  We have found that approximately 25-40% (Mintun et al., 2006, and unpublished data) of nondemented subjects have elevated PIB binding similar to that found by Price and Morris (1999) (Aim 2).  At the end of this project, it was too early to evaluate whether nondemented subjects with elevated PIB binding by PET have more rapid decline in cognitive function over time or increased rate of conversion to DAT (Aim 3). However, a preliminary cross-sectional analysis correlating neuropsychological scores with quantitative regional binding of PIB yielded several significant findings. For example there was highly significant inverse correlation of PIB binding in the temporal lobe region with the score on the Boston Naming Task (n = 29, r = -0.44, p = 0.016) as well as a significant correlation of PIB binding in the frontal lobe region with the score on the Crossing Off task (n = 29, r = 0.38, p = 0.043). We are considering the possibility that while the subjects are all nondemented, the elevated PIB binding may be associated with a subtle constellation of early changes in neuropsychometric performances. As we continue to collect a larger sample size (see “Resulting Grants” below) we will be able to make more definitive analyses.

SELECTED PUBLICATIONS

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Mintun M.A., LaRossa G.N., Sheline Y.I., Dence C.S., Yoon Lee S., 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;67:446-452.

Fagan A.M., Mintun M.A., Mach R.H., Lee S-Y, Dence C.S., Shah A.R., LaRossa G., Spinner M.L., Klunk W.E., Mathis C.A., DeKosky S.T., Morris J.C., and Holtzman D.M. Inverse relationship between in vivo amyloid imaging load and CSF Aβ42 in humans. Annals of Neurology, 2006, March; 59 512-519.

Klunk W.E., Engler H., Nordberg A., Wang Y., Blomqvist G., Holt D.P., Bergström M., Savitcheva I., Huang G.F., Estrada S., Ausén B., Debnath M.L., Barletta J., Price J.C., Sandell J., Lopresti B.J., Wall A., Koivisto P., Antoni G., Mathis C.A., and Långström B. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.  Ann Neurol, 2004; 55:306-319.

Storandt M., Grant E.A., Miller P.J., and Morris J.C.  Rates of progression in mild cognitive impairment and early Alzheimer's disease. Neurology, 2002; 59:1034-1041.

Morris J.C. and Price J.L.  Pathologic correlates of nondemented aging, mild cognitive impairment, and early stage Alzheimer's disease.  J Mol Neurosci. 2001; 17:2:101-118.

Buckner R.L., Snyder A.Z., Sanders A.L., Raichle M.E., and Morris J.C.  Functional brain imaging of nondemented and demented older adults.  J Cog Neuroscience 2000; 12:24-34.