23 Mar 2005

This is part 2 of the biomarker update from Sorrento.

Picture Power
Besides biochemistry and genetics, the search for early markers has focused heavily on brain imaging. Pittsburgh Compound-B (PIB) has broken new ground by lightening up amyloid deposits in the brain of AD patients. It is also said to distinguish better between AD and related dementias than does 18F-FDG PET, another imaging method that has shown promise and can inform the diagnosis at specialized medical centers. To become widely available, safer, and cost-effective, PIB needs to be coupled to a ligand other than 11C; alternatively, MRI-based tracers may be developed (see ARF related news story). For now, however, PIB continues to lead a growing pack of experimental amyloid dyes into uncharted human territory. The Alzheimer Research Forum has covered the testing of PIB extensively (see ARF recent conference update). Below is additional news from Sorrento.

Agneta Nordberg of the Karolinska Institute in Stockholm, Sweden, heads the group that began the first prospective human study of PIB at the PET Center in Uppsala. In Sorrento, she presented data of a follow-up measurement of a group of 16 AD patients 1.5 to 2.5 years after their first PIB imaging session. Patients whose cognitive scores declined during this time showed an increase in PIB retention at the second measurement, while those whose cognition stayed stable also had largely stable PIB retention. People whose cognition worsened over the course of this time started the study with higher PIB binding values than did people who remained stable. Together, this suggests that PIB retention and, by extension, amyloid load is correlated with performance and that amyloid deposition precedes the clinical progression of AD, said Nordberg, but she added that her speculative interpretation needs more data and statistics to back it up. Nordberg said she would reveal new data on the small prospective MCI cohort in the study when that group contained at least 20 people. The burning question there is whether PIB can predict who among those with a diagnosis of MCI will develop AD, and when. “We are still at the beginning of this research. New ligands will come up and new methods to evaluate them,” concluded Nordberg.

Chris Rowe preceded his presentation of initial data from his group’s PIB studies by deploring that the commercial licensing agreement for PIB has made it more difficult for academic scientists to test PIB more broadly. To date, only five out of many more qualified academic PET centers have joined the Swedish teams and the original Pittsburg team in testing PIB, said Rowe. They are in Toronto, London, Turku/Finland, Washington University in St. Louis, Missouri, and Austin Hospital in Heidelberg, Australia.

Working at this latter center on the outskirts of Melbourne, Rowe collaborated with others at Monash University and the University of Melbourne to start a prospective study comparing MRI, FDG-PET and PIB-PET in people with AD, DLB, and controls. A neuropsychiatric test battery, as well as plasma Aβ and ApoE genotyping, are part of the study. Five patients with mild AD who have been imaged to date all have abnormal PIB scans with high PIB retention in the cortex, said Rowe. Of the five control subjects, four show low PIB binding. A 78-year-old woman, who complained about being “less sharp” than before but has an abnormally low score only in one verbal fluency test, retained moderate amounts of PIB in her cortex, said Rowe.

Four patients enrolled so far into the LBD group all have advanced dementia and show PIB retention in a pattern that appears distinct from that of AD, said Rowe. LBD patients have lower overall uptake levels than do AD patients at the same stage of disease. Moreover, they show more diffuse retention, with a significant PIB signal in areas that are relatively spared in AD, such as the occipital lobe and primary sensory and motor cortex. By testing PIB and FDG-PET side-by-side, this study, as well as Nordberg’s, will try to find out whether amyloid PET or PET based on glucose metabolism is more sensitive at picking up early stages of AD.

No matter who wins this particular contest, both methods require that the patients agree to flood their veins with radioactive tracers for several hours. Researchers are trying to find other methods that dispense with this infusion. In Sorrento, Norbert Schuff of the University of California, San Francisco, introduced early data on arterial spin-labeling perfusion MRI, which lights up under-perfused brain areas without an injection. Schuff suggested that once the signal-noise ratio of this method has improved, it, too, could help the clinician perform a differential diagnosis, because it generated different anatomical patterns of insufficient perfusion between related neurodegenerative conditions (see also Johnson et al., 2005). A broad-based multinational initiative has begun to validate the best among the multitude of promising approaches that neuroimaging has produced in recent years. Check back tomorrow for a news story on this big-science slice of the broader biomarker story.—Gabrielle Strobel.

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References

News Citations

1. Visualizing Success with MRI of Amyloid Plaques in Live Mice 13 Mar 2005
2. Philadelphia: All Eyes on PIB Imaging—Is It Coming Along? 27 Jul 2004

Paper Citations

1. Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ, Gorno-Tempini ML, Schuff N. Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology. 2005 Mar;234(3):851-9. PubMed.

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