. Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain. 2006 Nov;129(Pt 11):2856-66. PubMed.


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  1. There are many unanswered questions about the new amyloid imaging technologies for Alzheimer disease (AD). Central among these are how the retention of an amyloid imaging tracer varies over time in an individual, and whether the presence of amyloid-β (Aβ) deposition heralds inevitable Alzheimer disease. This study of Engler et al. in the July issue of Brain represents a landmark study addressing the first question of longitudinal changes in Aβ load in AD patients. Several studies have shown that the test/re-test reproducibility of one PET Aβ tracer, Pittsburgh Compound-B (PiB), is very good, typically in the range of 4-5 percent in brain areas where Aβ deposition is found in AD (Price et al., 2005). This suggests that any time-dependent change in tracer retention that is greater than 5 percent is due to changes in Aβ load and not variability of the technique. This statement is true of a range of analytical outcome measures that allow PiB-PET technology to be applied in a variety of simplified study designs (Lopresti et al., 2005).

    Cross-sectional studies using PiB suggest that there is little increase in Aβ load from early stages of cognitive impairment (e.g., mild cognitive impairment, or MCI) through mild to moderate stages of AD (Klunk et al., 2004; Lopresti et al., 2005; Price et al., 2005). These studies predict that much of the Aβ deposition seen in individuals with AD or MCI occurs at an even earlier, pre-symptomatic stage, and that a maximum or equilibrium level of Aβ plaques can be reached early in the pathological course of AD. However, cross-sectional studies can be misleading because individual differences are averaged out. Therefore, this study by Engler et al. is of great interest and importance, because it examines PiB retention longitudinally in the same 16 AD subjects who were studied in the original description of PiB-PET imaging (Klunk et al., 2004). Engler et al. were successful in obtaining baseline and follow-up PiB and [F-18]2-fluoro-2-deoxy-D-glucose (FDG) imaging in 13 of these subjects over an average inter-scan interval of 2 years and report these data in this study. While we also provided comments of a more technical nature that accompany the Engler et al. manuscript in Brain, we have been asked to provide comments from a broader perspective for the Alzheimer Research Forum.

    Knowledge of the changes in PiB retention (and presumably Aβ plaque deposition) over time carry several implications. If Aβ load increases significantly over time during the clinical phase of AD, then it makes sense to institute therapies during this clinical phase that halt or slow Aβ production and accumulation. Examples of this therapeutic approach include secretase inhibitors and therapies that help clear existing Aβ deposits, such as anti-Aβ immunotherapies. In addition, demonstration of an increase in Aβ load over time in patients with clinical AD implies that amyloid imaging might be useful in monitoring the efficacy of Aβ production inhibitors as well as Aβ clearing agents (i.e., one could measure a slowing or halting of Aβ buildup).

    If there is little Aβ deposition over time in an individual during the clinical phase of AD (i.e., the Aβ deposition phase of AD is already complete), expectations would be different. It would still seem beneficial to use Aβ-clearing therapies, and amyloid imaging could still prove useful in monitoring efficacy as the existing plaques were cleared. The expected effect of blocking Aβ production would be less clear. If Aβ plaques are relatively stable, blockade of new Aβ production could lower monomeric and, perhaps, oligomeric forms of Aβ without affecting plaque load. Given the increasing evidence for the toxicity of soluble, oligomeric forms of Aβ (Klein, 2006; Lesne et al., 2006), use of Aβ production inhibitors would appear an effective therapeutic strategy even if Aβ plaque load was unaltered. However, in this case, amyloid imaging would be of little use in monitoring the efficacy of drugs that inhibit Aβ production since these drugs would have no effect on the stable, fibrillar Aβ deposits measured by tracers like PiB.

    Experimental evidence suggests that Aβ plaques are not stable structures and that they can be formed and cleared in a matter of days or weeks (Bacskai et al., 2001; Christie et al., 2001). Cerebrovascular amyloid appears to be equally dynamic (Robbins et al., 2006). Under these dynamic conditions, an apparent stability in Aβ plaque load may be a result of a relatively stable equilibrium state that obscures the underlying dynamic process of continued Aβ synthesis, aggregation, deposition, and clearance. In AD brain, the insoluble pool of Aβ typically represents 96-99 percent of the total (Kuo et al., 1996) and, therefore, could represent a large pool for the regeneration of oligomeric and monomeric forms of Aβ. Under these circumstances, in order for Aβ production inhibitors to have a useful effect, the entire equilibrium would need to be shifted, and would need to result in a decrease in plaque load over time. This effect may be amenable to monitoring with amyloid imaging techniques.

    The natural history of Aβ deposition in AD must be understood before we can predict the expected effect of anti-Aβ therapies and the potential usefulness of amyloid imaging as a marker of efficacy for these experimental therapies. The study by Engler et al. is an important first step. Engler et al. concluded that there was little, if any, increase in PiB retention over time in their series of AD patients. At the same time, there was a 20 percent decrease in regional cerebral metabolic rate for glucose (rCMRglc; determined with FDG-PET) in cortical brain areas. They conclude that, “...anti-Aβ therapies will need to induce a significant decrease in Aβ load in order for PiB-PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer’s disease.” This conclusion seems well-supported by the group data presented. However, Engler et al. might have taken greater advantage of their longitudinal data by discussing the changes in individual subjects. They do compare subgroups of AD patients (four who had significant cognitive decline and nine who were clinically stable). Although PiB retention was higher in the declining group at baseline and follow-up, Engler et al. did not report any difference in interval change in PiB retention between these groups.

    Engler et al. did not directly report the trajectories of PiB retention and rCMRglc for individual subjects over time, but these data can be determined from their Figure 2 and are shown below.


    Individual trajectories of PiB retention and rCMRglc in the parietal cortex of the 13 subjects with both baseline and follow-up PiB and FDG imaging data.
    Increasing PiB retention (i.e., worsening disease) is shown on the y-axis in the units used by Engler et al. Decreasing metabolism (i.e., worsening disease) is shown on an inverted scale on the x-axis. The numbers in circles correspond to the individual subjects from the Engler et al. study and represent the baseline PiB and FDG values; the arrows point toward the follow-up values. The shaded rectangles indicate the 4.1 percent test/re-test variability of PiB-PET in the parietal lobe. Red arrows (and orange rectangles) indicate the four clinically declining AD subjects (2, 3, 7, and 11). All other subjects were clinically stable, but green arrows emphasize the two subjects (5 and 15) with paradoxical improvements in both PiB retention (decreased) and cerebral metabolism (increased). Subjects 2, 13, and 16 showed essentially no change in PiB retention, but the other subjects showed changes greater than to be expected from test/re-test variability alone.

    It is readily apparent that most subjects (7 of 13) show both an increase in PiB retention and a decrease in metabolism over time. This appears to be hidden in the grouped analyses by relatively large decreases in PiB retention in four subjects (3, 5, 7, and 15). The paradoxical changes in subjects 5 and 15 (decreased PiB retention and increased metabolism) are difficult to explain, as both changes are contrary to that expected in AD. However, the decreases in PiB retention coupled to decreases in metabolism in subjects 3 and 7 may relate to the phenomenon previously described in Down syndrome and AD. A prior study indicated that Aβ deposits decline late in the course of AD in Down syndrome (Wegiel et al., 1999), and another suggested that the same phenomenon may occur in sporadic AD (Hyman et al., 1993). Thus, it is intriguing that subjects 3 and 7, who had the most advanced disease at baseline and who also showed significant cognitive worsening over the two-year follow-up, were the only subjects who had both decreased PIB retention and rCMRglc. In summary, amyloid imaging is still an emerging technology, and there is much to learn. Engler et al. add important data to the field and suggest that while Aβ deposition (measured by PiB retention) may increase slightly in individual subjects over time, there is relatively little increase during the clinical phase of AD. This finding is consistent with previous cross-sectional studies that found relatively high PiB retention in many MCI subjects (Lopresti et al., 2005; Price et al., 2005). One fundamental implication of these findings is very important: by waiting until clinical symptoms of AD (or even MCI) are present, we may miss the optimal period for treatment with anti-Aβ therapies. It is clear that pre-existing neurofibrillary changes and cell death are not reversed by anti-Aβ immunotherapy, even when there is evidence of substantial Aβ clearance (Ferrer et al., 2004; Masliah et al., 2005; Nicoll et al., 2003). Even if current clinical trials of anti-Aβ therapies show effective removal of Aβ but relatively modest clinical effects [the AN-1792 active immunotherapy trial was interrupted too early to provide definitive answers, but tended in this direction (Ferrer et al., 2004; Gilman et al., 2005; Masliah et al., 2005; Nicoll et al., 2003)], these same therapies might have significant effects on clinical outcome if instituted much earlier in the pathogenic cascade. Given the current lack of truly effective therapies for AD, current trial strategies must move into MCI and even pre-symptomatic AD so as not to miss opportunities to effectively treat this devastating disorder. Amyloid imaging could prove of great help in developing such studies.


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