In the opening scenes of Tim Burton's iconic movie Big Fish, an evil witch invites a group of boys to look into her glass eye to show them how they will die. The only taker is the young hero, Edward Bloom, who (unlike the audience) witnesses his future death. The film unfolds to recount Edward's extraordinary exploits as an adult, empowered by knowledge that each current crisis before him – whether confronting a giant, a war, or a belligerent rival – will not be his end. He is empowered by knowing the future, even though it is unalterable.

Another well-known story is that of Ebenezer Scrooge, visited by an apparition, the Ghost of Christmas Future. Scrooge is given a look into his horrible death but, unlike Edward Bloom, Scrooge's fate can be changed if he mends his ways.

Two different looks into the future; in one case the future is mutable and in the other it is not.

On April 6, 2012, the FDA approved Florbetapir-F18, a PET ligand, for the detection of beta amyloid aggregates. Florbetapir and the more widely studied Pittsburgh-B compound (PIB) are probably similar; both measure aggregated amyloid. Because it uses a flourinated F-18 tracer, Florbetapir has a longer half-life than PIB C-11, making it a more practical radioligand for widespread use. It is clear that a strongly positive Florbetapir scan correlates well with the presence of amyloid deposition at autopsy, and in a patient with established dementia or early cognitive complaints, a negative scan makes Alzheimer disease (AD) highly unlikely. However, in the large scale study of Florbetapir published last year,1 there was substantial interobserver variability in terms of what constitutes a positive scan, and thus uncertain sensitivity, specificity and reproducibility. In a practical sense, it is likely that many scans will be inconclusive.

Even less clear and more controversial is the ability of Florbetapir to predict future cognitive outcomes in currently healthy individuals. In a longitudinal study from the Alzheimer Disease Neuroimaging Initiative (ADNI), nearly one third of cognitively normal elderly individuals were Florbetapir positive at baseline, compared with more than 50% of patients diagnosed with mild cognitive impairment (MCI) and more than 75% with AD;2 these estimates are similar to those reported earlier with Florbetapir3 and with PIB.4 In the ADNI study, ten of seventy-six cognitively normal individuals converted to MCI/AD over an average period of 4 years; seven of the ten had positive scans at baseline, but three did not. Of those cognitively normal but Florbetapir positive at baseline, 70% progressed to MCI/AD compared to only 6% of those whose scans were negative. Individuals with positive scans also experienced a greater annual decline in cognitive function even if they did not satisfy criteria for MCI/AD, suggesting that Florbetapir is measuring something important even in healthy elderly.

While many experts believe that essentially all “cognitively normal” elderly individuals who are Florbetapir positive will ultimately advance to MCI/AD, thus far, experience with long-term follow-up is extremely limited and caution is warranted. Hypothetically, there are likely some individuals who either are resistant to amyloid deposits or may have enough cognitive reserve that this never impacts them. Far more data will be needed before definitive answers, including the sensitivity and specificity of a Florbetapir scan for predicting clinical AD, are known.

What are the uses of a positive scan in a cognitively normal individual? For some, a positive result might encourage lifestyle changes, perhaps including diet (even a Mediterranean diet5), regular exercise, and cognitive training, but perhaps these adjustments should be undertaken irrespective of PET findings. Furthermore, the protective effect of these health-promoting lifestyle measures is modest at best. Absent an effective disease-modifying treatment for AD, the value of an improved risk assessment diagnostic is debatable, and potentially harmful.

The analogies to the APOE genotyping story, now decades old, are striking. When first developed, APOE genotyping was touted by the popular press as an accurate screen for AD with an initial rush for testing. These hopes were tempered by data questioning its value. Positive amyloid scans likely predict conversion to AD in cognitively normal individuals at least as well as the presence of two copies of APOE4, but the implications of positive tests are really no different today.

In the coming months, we are likely to see a massive roll-out of Florbetapir scanning in different settings. This may represent a meaningful advance for the evaluation of symptomatic MCI or dementia, though results may not alter treatment in many patients. It is also certain that Florbetapir will become extremely valuable as a surrogate measure in clinical trials testing new therapies for AD. Beyond these uses, however, the indications for Florbetapir scanning seem uncertain. For-profit diagnostic facilities are likely to advertise their new capability quickly to asymptomatic individuals, encouraging them to learn their amyloid status on a right-to-know basis, even though it is not likely at this time that any insurers, including CMS, will pay for this test. Analogous to diagnostic whole-body and cardiac scans, or results from do-it-yourself genetic testing, clinicians are likely to be faced with many requests to assess the significance of positive amyloid scans from their healthy, frightened patients, most of whom did not receive appropriate pre-test counseling as to the risks (including those to future insurance coverage) of a positive test.5 Furthermore, the costs of the tests—whether borne by the patient or society—may be substantial, particularly given the limited value of the information.

At the current time, Florbetapir provides a glimpse into a future that is today largely immutable. However, with hopeful prospects for development of effective disease modifying therapies for AD on the horizon, this could change in the near future, and more accurate diagnoses and markers of progression in clinical trials will certainly increase power and hasten progress. All of us await with anticipation the results of an amyloid-targeted immunotherapy trial with the monoclonal antibody bapineuzumab expected later this year, and other late stage therapeutic trials for AD also seem promising. It goes without saying that the prospects of effective therapy against AD will be a game-changer for neurology, and will transform the value of knowing one's amyloid status. Rather than providing a glimpse into an immutable future, a positive Florbetapir scan would then lead to actionable, preventive measures. When debated at a recent Annals editorial meeting, the majority of us (mostly presymptomatic) decided we would rather not be tested today, though one said he would travel to more exotic places if he knew he were positive.

Stephen L. Hauser, MD, S. Andrew Josephson, MD and S. Claiborne Johnston, MD, PhD Editors


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