Researchers develop a new method for imaging amyloid deposits in Alzheimer’s disease

Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt GP, et al. (2004). Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B. Annals of Neurology, 55:306-319.

Researchers at the University of Pittsburgh and in Sweden (Uppsala University, the Karolinska Institute, and Huddinge University Hospital) have just published a study of a new method for imaging amyloid in Alzheimer’s disease. The study is potentially an important development in understanding how abnormal amyloid build up relates to the symptoms of Alzheimer’s disease.

At the cellular level, Alzheimer’s disease (AD) is characterized by two abnormalities: formation of neurofibrillary tangles due to an abnormality in a protein called tau; and buildup of another protein called amyloid (see figure 1). There is considerable interest in the relationship between amyloid and the symptoms of AD and amyloid has been identified as a potential target for treatment, although no such treatments have emerged to date. Amyloid is produced normally in the body. One particular fragment of amyloid called beta-amyloid is broken down and removed from the brain. However, in AD, beta amyloid is processed abnormally and these fragments accumulate together to form insoluble amyloid plaques that are thought to contribute to nerve cell damage. The exact mechanism that causes the amyloid abnormalities in Alzheimer’s disease is not fully understood. In AD, amyloid plaques spread to certain brain regions and become more densely concentrated as the disease progresses. However, some brain areas remain relatively unaffected by amyloid deposits in AD. Previously, it was only possible to measure amyloid concentration in brain slices taken after death.

Figure 1: Drawing showing brain tissue in a normal brain and in Alzheimer’s disease. Note the presence of neurofibrillary tangles and amyloid plaques in the AD brain. (From: http://www.ahaf.org/alzdis/about/AmyloidPlaques.htm)

The goal of the research project was to develop a compound that could be used to image amyloid plaques in living patients. The research team, lead by William E Klunk, MD from the University of Pittsburgh, developed a chemical compound called Pittsburgh Compound-B (PIB). The compound was designed to enter brain tissue, selectively bind with amyloid, be imaged using positron emission tomography (PET), and then be removed relatively quickly. PET is a technique that uses very mild radioactive compounds and a specialized camera to take pictures of activity in the brain.

The study involved 16 patients with Alzheimer’s disease (AD) and 9 healthy control subjects (6 older controls and 3 young controls). All subjects received intravenous administration of PIB and then received PET imaging. PET images showed that compared with the control subjects, the patients with AD showed that PIB bound to brain regions known to contain large amounts of amyloid in AD (see figure 2). In contrast, PIB did not bind to brain regions that are relatively unaffected by amyloid deposition. In these unaffected regions, the amount of PIB retained did not differ significantly between AD patients and control subjects.

Figure 2. Bright areas in the top right show PIB binding in AD. Light blue areas in the bottom right (arrows) show areas of hypometabolism on an FDG glucose PET scan in AD.

This “proof-of-concept” study demonstrated that use of PIB with PET imaging is a potentially useful method of visualizing and studying amyloid deposits in patients with AD. PIB represents the third attempt for imaging amyloid deposits in AD. In one study, there was no evidence that the compound was taken up by brain tissue. Another compound, developed by researchers at UCLA, had retention in some brain areas that might not be associated with high concentrations of amyloid. The authors caution that more work needs to be done and that it is premature to consider PIB as a useful as a method of diagnosing Alzheimer’s disease. But PIB might be useful for understanding the relationship between the clinical symptoms of AD and amyloid deposits. It could shed light on how amyloid buildup relates to the progression of symptoms. If the results are confirmed in subsequent studies, then this imaging technique might eventually be used in the future to test the efficacy of treatments aimed at controlling amyloid buildup in AD.

Figure 3. Brain images of a healthy control and patient with AD in axial view (top two rows) and sagittal view (bottom two rows). Rows 1 and 3 are the control subject and rows 2 and 4 are the AD subject. Bright colors represent regions where PIB was retained. These areas correspond to brain regions known to have high levels of amyloid in AD (Klunk et al., Ann Neurol, 2004; 55:312).