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Reporting in this week’s PNAS early online edition, Brian Bacskai and colleagues from Massachusetts General Hospital, Charlestown, and Bill Klunk and colleagues at the University of Pittsburgh, Pennsylvania, show that they can image the uptake, labeling of amyloid plaques, and subsequent release of the thioflavin derivative Pittsburgh compound B (PIB). The study, conducted on mice and reported at The Living Brain and Alzheimer's Disease conference last March (see ARF related news story), holds out the promise for a quick diagnosis of Alzheimer’s disease (AD) in humans.

 

image This four-dimensional image represents the XYZ axes and time in a tiny area of cortex from a live APP-transgenic mouse minutes after it has received an injection of the fluorescent amyloid marker PIB into its tail vein...
(See a larger version of this image and the rest of the caption.)

Currently, most AD patients are diagnosed through clinical examinations, and the only definitive means of diagnosis is postmortem pathology. Though great strides have been made in the use of various imaging techniques to test and monitor the symptoms of AD (see ARF related news story), some of them measure neurodegeneration or metabolic changes that could be attributed to any number of neurodegenerative diseases. By being able to reversibly label amyloid plaques directly, the researchers have developed the basis for a diagnostic test specifically for AD.

The authors used multiphoton microscopy to trace the fluorescence of PIB in the brains of mice that had a small section of the cranium replaced with a glass coverslip. Within seconds of injecting the compound into the tail vein, the fluorescence appeared in the blood vessels and capillaries of the brain, and soon after, could be seen diffusing through the small capillaries into the neuropil.

The authors found that in normal mice, PIB sails through the brain, leaving it after about 25 minutes. However, in Tg2576 mice, which express human mutant AβPP and mimic the amyloid deposition seen in humans, the compound is taken up by both plaque and vascular amyloid, which retard its diffusion. In normal mice, uptake is almost instantaneous, while in the Tg2576 mice, peak labeling occurred after about 20 minutes and persisted. In fact, plaques could still be detected up to three days after injection, despite rapid clearance of PIB from amyloid-free tissue.

To ensure that PIB specifically labels amyloid, Bacskai and colleagues first treated animals with PIB, and then postmortem with thiazine red R (like thioflavin S, the latter labels plaques and cerebral amyloid angiopathies). In tissue sections of whole brain, the fluorescence of the two compounds overlapped perfectly, indicating that in-vivo labeling with PIB accurately reflects the amyloid load in the brain.

For humans, that hope is that carbon-11-labeled PIB will be a useful tracer for positron emission tomography. However, as the authors point out, the resolution of PET scans is not as fine as that of multiphoton microscopy and the “sensitivity of PIB detection of amyloid with PET scanning will need to be addressed independently."-Tom Fagan.

Reference:
Bacskai BJ, Hickey GA, Skoch J, Kajdasz ST, Wang Y, Huang G-F, Mathis CA, Klunk WE, Hyman BT. Four-dimensional imaging of brain entry, amyloid-binding, and clearance of an amyloid-beta ligand in transgenic mice using multiphoton microscopy. PNAS early online edition. 2003 September 22. Abstract

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  1. I think this is an excellent and exciting paper. Hopefully, direct imaging of AD pathology is just around the corner for patients. The compounds developed by Dr. Klunk and used by Dr. Hyman work extremely well for in-vivo two-photon work, and show promise in human PET studies. Up to now, imaging studies of AD pathology have used indirect methods that correlate various changes (entorhinal cortex volumes, 2DG-PET, etc.) to lesions. However, the development of methodologies that directly image lesions will be an important advance for both diagnosis and early treatment. We are working on developing ligands that could be used with magnetic resonance imaging, which has a better resolution than PET (see Wadghiri et al., 2003), and these methods also show promise.

  2. This is an extremely exciting paper, which reports outstanding work from the group of investigators in Pittsburgh and their collaborators around the world. There is considerable evidence that the protein called amyloid may play an important role in the development of Alzheimer's disease. The results shown in this paper are a major step forward in the development of tools to image amyloid in the human brain.

    The authors should be commended for their very careful step-by-step approach to the problem. Although considerably more work needs to be done in this area, this work is extremely promising for the development of a tool which could be used for diagnosis, monitoring the effects of treatment, and even possibly early detection of Alzheimer's disease.

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References

News Citations

  1. Bill Klunk Reports from Paris on The Living Brain and Alzheimer’s Disease
  2. PET Diagnosis Poised for Prime Time? FDA Wants Consensus, Better Trials

Paper Citations

  1. . Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12462-7. PubMed.

Other Citations

  1. See a larger version of this image

Further Reading

Papers

  1. . Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12462-7. PubMed.

News

  1. Stockholm: Visualizing Amyloid Biggest Draw at Imaging Symposium, Consensus Sought on Validation
  2. ApoE Catalyst Conference Explores Drug Development Opportunities
  3. Seeing Alzheimer’s: Advances in Brain Mapping Bring Goal a Step Closer
  4. Mutant AβPP Retards Growth in Hippocampus before Plaques Form
  5. Stockholm: Pictures at an Exhibition

Primary Papers

  1. . Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12462-7. PubMed.