Simple In Vivo PET Measure of Amyloid Binding in AD

Summary

Principal Investigator: Julie C Price
Abstract: DESCRIPTION (provided by applicant): At present, the definitive diagnosis of Alzheimer's disease (AD) is based on the pathologic confirmation of amyloid plaques and neurofibrillary tangles in the cerebral cortex. Over many years, our research efforts have been directed toward the development of non-invasive methods for the in vivo measurement of amyloid plaques. Toward this goal, our group recently collaborated with researchers in Uppsala, Sweden, to perform the first human positron emission tomography (PET) studies of a new amyloidbinding radiotracer, named PIB (Pittsburgh Compound B). These first human studies demonstrated high PIB retention in AD subjects (n=9) in brain areas known to have high amyloid levels in AD (relative to controls, n=5). The next step in our efforts is to establish the validity of the PIB PET methodology and to determine a valid and simple method for potential clinical use. The central goal of this application is to validate the PIB PET methodology and identify a simple PIB measure of amyloid-binding that is feasible for routine use. Toward this goal, PIB PET studies will be acquired in 3 subject groups: mild-to-moderate AD dementia (n=12), mild cognitive impairment (n=12), and elderly controls (n=12). PIB localization will be related to measures of brain glucose metabolism (using [18F]FDG), which has been extensively used as a metabolic index of AD. Validation will include acquisition of [15O]water PET data to exclude the influence of variations in blood flow on PIB binding. Structural MRI data will be acquired in all subjects to provide anatomical guidance for the PET data analyses. Our first aim is to identify an optimal fully-quantitative (arterial blood) PIB PET method. The second aim is to choose a valid and simple (no blood sampling) PIB PET method based upon the fully-quantitative data and an iterative evaluation of observed and computer-simulated PIB data. The simple method will allow rapid generation of robust image maps of amyloid binding throughout brain. The final aim is to relate anatomically standardized maps of amyloid binding to maps of cerebral metabolism. This research will provide important groundwork to support the use of the PIB measure of amyloid binding in early and pre-clinical diagnosis of AD and potentially accelerate the development and evaluation of important new therapies for dementia.
Funding Period: 2004-05-13 - 2009-04-30
more information: NIH RePORT

Top Publications

  1. pmc In vivo assessment of amyloid-β deposition in nondemented very elderly subjects
    Chester A Mathis
    Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Ann Neurol 73:751-61. 2013
  2. pmc Development of positron emission tomography β-amyloid plaque imaging agents
    Chester A Mathis
    Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Semin Nucl Med 42:423-32. 2012
  3. pmc Application of copulas to improve covariance estimation for partial least squares
    Gina M D'Angelo
    Division of Biostatistics, Washington University School of Medicine, St Louis, MO, U S A
    Stat Med 32:685-96. 2013
  4. pmc Molecular brain imaging in the multimodality era
    Julie C Price
    Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    J Cereb Blood Flow Metab 32:1377-92. 2012
  5. pmc Inter-rater reliability of manual and automated region-of-interest delineation for PiB PET
    Bedda L Rosario
    Department of Radiology, University of Pittsburgh School of Medicine, Presbyterian University Hospital, B 938, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    Neuroimage 55:933-41. 2011
  6. pmc Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease
    Clayton A Wiley
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
    Arch Neurol 66:60-7. 2009
  7. pmc Consideration of optimal time window for Pittsburgh compound B PET summed uptake measurements
    REBECCA L MCNAMEE
    Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    J Nucl Med 50:348-55. 2009
  8. pmc Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease
    Eric M Reiman
    Banner Alzheimer s Institute and the Positron Emission Tomography Center, Good Samaritan Regional Medical Center, Phoenix, AZ 85006, USA
    Proc Natl Acad Sci U S A 106:6820-5. 2009
  9. pmc Amyloid imaging in mild cognitive impairment subtypes
    David A Wolk
    Alzheimer s Disease Research Center, University of Pittsburgh, Pittsburgh, PA 19104, USA
    Ann Neurol 65:557-68. 2009
  10. pmc Relationships between biomarkers in aging and dementia
    W J Jagust
    Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94620, USA
    Neurology 73:1193-9. 2009

Scientific Experts

Detail Information

Publications24

  1. pmc In vivo assessment of amyloid-β deposition in nondemented very elderly subjects
    Chester A Mathis
    Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Ann Neurol 73:751-61. 2013
    ....
  2. pmc Development of positron emission tomography β-amyloid plaque imaging agents
    Chester A Mathis
    Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Semin Nucl Med 42:423-32. 2012
    ..It is likely that the full clinical impact of these imaging agents will be realized by identifying presymptomatic subjects who would benefit from early drug treatments with future disease-modifying AD therapeutics...
  3. pmc Application of copulas to improve covariance estimation for partial least squares
    Gina M D'Angelo
    Division of Biostatistics, Washington University School of Medicine, St Louis, MO, U S A
    Stat Med 32:685-96. 2013
    ..Simulation studies show that the proposed estimator is an improvement over the standard estimators of covariance. We illustrate the methods from the motivating example from a study in the area of Alzheimer's disease...
  4. pmc Molecular brain imaging in the multimodality era
    Julie C Price
    Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    J Cereb Blood Flow Metab 32:1377-92. 2012
    ....
  5. pmc Inter-rater reliability of manual and automated region-of-interest delineation for PiB PET
    Bedda L Rosario
    Department of Radiology, University of Pittsburgh School of Medicine, Presbyterian University Hospital, B 938, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    Neuroimage 55:933-41. 2011
    ....
  6. pmc Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease
    Clayton A Wiley
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
    Arch Neurol 66:60-7. 2009
    ..Because postmortem histopathological analyses are limited to single end-stage assessment, the time course and nature of this relationship are not well understood...
  7. pmc Consideration of optimal time window for Pittsburgh compound B PET summed uptake measurements
    REBECCA L MCNAMEE
    Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    J Nucl Med 50:348-55. 2009
    ..In this work, regional PiB SUVRs were examined across 9 time windows to select the window that provided the best trade-offs between bias, correlation, and effective contrast...
  8. pmc Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease
    Eric M Reiman
    Banner Alzheimer s Institute and the Positron Emission Tomography Center, Good Samaritan Regional Medical Center, Phoenix, AZ 85006, USA
    Proc Natl Acad Sci U S A 106:6820-5. 2009
    ....
  9. pmc Amyloid imaging in mild cognitive impairment subtypes
    David A Wolk
    Alzheimer s Disease Research Center, University of Pittsburgh, Pittsburgh, PA 19104, USA
    Ann Neurol 65:557-68. 2009
    ....
  10. pmc Relationships between biomarkers in aging and dementia
    W J Jagust
    Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94620, USA
    Neurology 73:1193-9. 2009
    ..Relationships between biomarkers and with disease severity are incompletely understood...
  11. pmc Basal cerebral metabolism may modulate the cognitive effects of Abeta in mild cognitive impairment: an example of brain reserve
    Ann D Cohen
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
    J Neurosci 29:14770-8. 2009
    ....
  12. pmc Frequent amyloid deposition without significant cognitive impairment among the elderly
    Howard Jay Aizenstein
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Arch Neurol 65:1509-17. 2008
    ....
  13. pmc The future of amyloid-beta imaging: a tale of radionuclides and tracer proliferation
    William E Klunk
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Curr Opin Neurol 21:683-7. 2008
    ....
  14. ncbi Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B
    Julie C Price
    Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
    J Cereb Blood Flow Metab 25:1528-47. 2005
    ..This study also showed that it is feasible to perform quantitative PIB PET imaging studies that are needed to validate simpler methods for routine use across the AD disease spectrum...
  15. ncbi Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis
    Brian J Lopresti
    Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
    J Nucl Med 46:1959-72. 2005
    ..This work reports on simplified methods of analysis for human PIB imaging...
  16. ncbi Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease
    Scott K Ziolko
    Department of Radiology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Rm B 938, PA 15213, USA
    Neuroimage 33:94-102. 2006
    ..These results indicate that voxel-based methods will be useful for future larger longitudinal studies of amyloid deposition that could improve AD diagnosis and anti-amyloid therapy assessment...
  17. pmc Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees
    William E Klunk
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
    J Neurosci 27:6174-84. 2007
    ..The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms...
  18. pmc Registration-based method for determining relative PET/MR left-right image orientation
    C M Laymon
    Department of Radiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    Neuroimage 40:213-6. 2008
    ..In 122 studies using data with known orientations, 100% accuracy of the method was observed...
  19. pmc Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease
    Milos D Ikonomovic
    Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Brain 131:1630-45. 2008
    ..The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Abeta plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Abeta plaque burden...
  20. pmc Assessment of parameter settings for SPM5 spatial normalization of structural MRI data: application to type 2 diabetes
    Bedda L Rosario
    Department of Biostatistics, University of Pittsburgh, Graduate School of Public Health, 130 DeSoto Street, 326 Parran Hall, Pittsburgh, PA 15261, USA
    Neuroimage 41:363-70. 2008
    ..These findings are relevant for studies of structural brain alterations that may occur in normal aging, chronic medical conditions, neuropsychiatric disorders, and neurodegenerative disorders...
  21. pmc Imaging Alzheimer pathology in late-life depression with PET and Pittsburgh Compound-B
    Meryl A Butters
    Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213, USA
    Alzheimer Dis Assoc Disord 22:261-8. 2008
    ..Our findings are consistent with and supportive of the hypothesis that depression may herald the development of AD in some individuals...
  22. pmc Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer's disease with Pittsburgh Compound B
    Cyrus A Raji
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 2593, United States
    J Neurosci Methods 172:277-82. 2008
    ..02, p=0.01) and anterior ventral striatum [t(9)=2.37, p=0.04] in AD. No group differences (AD versus MCI) were detected in laterality [F (1, 15)=0.15, p=0.7] or asymmetry [F (1, 15)=0.7, p=0.42]...
  23. pmc Whatever happened to Pittsburgh Compound-A?
    William E Klunk
    Department of Psychiatry and Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Alzheimer Dis Assoc Disord 22:198-203. 2008
  24. ncbi Imaging technology for neurodegenerative diseases: progress toward detection of specific pathologies
    Chester A Mathis
    Department of Neurology, University of Pittsburgh and Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213, USA
    Arch Neurol 62:196-200. 2005
    ....