29 Jan 2013

Since the FDA approved the Aβ imaging agent florbetapir (Amyvid®) last April, academics and doctors have debated how it should be used (see ARF related news story). At that time, the Society of Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association assembled an Amyloid Imaging Taskforce (AIT) to devise recommendations for clinical practice (see ARF related news story). AIT co-chair Keith Johnson presented those guidelines at the 7th Human Amyloid Imaging meeting held in Miami, Florida, 16-18 January 2013. In a nutshell, the task force concluded that patients with objectively measured cognitive problems or unusual dementia presentations would benefit from amyloid imaging, and that only dementia experts should prescribe such scans. “These guidelines are an excellent start,” said Stephen Salloway, Brown University, Providence, Rhode Island. “They are well thought out and will be useful for third-party payers and clinicians.” They were formally published January 28 in Alzheimer's & Dementia and in the Journal of Nuclear Medicine. The 13 AIT members coauthored the papers, which are freely available online. Physicians have also been asking whether amyloid imaging changes patient management or diagnosis. In Miami, researchers presented two studies that took an initial stab at addressing these questions.

The ability to detect brain amyloid by positron emission tomography has left some doctors and patients with a dilemma. Many cognitively normal people accumulate Aβ in their brains, but researchers are still unsure what that means for their future brain health. On top of that, no treatment exists to stop or reverse Aβ buildup, and it is unclear as yet whether amyloid scans improve patient care (see ARF related news story). Because of these uncertainties, some researchers have questioned if amyloid scans are even ethical. Against that backdrop, the AIT put together a set of criteria for responsible use of the technology.

The committee decided that current data support amyloid imaging in three main groups: patients with memory complaints who show measurable impairment on standard cognitive and memory tests; people diagnosed with possible AD but who have an unusual clinical presentation; and people who have progressive dementia before age 65. In all these cases, imaging can reveal if Aβ accumulation underlies the symptoms.

The committee recommends against scanning when a clinical benefit seems unlikely. People falling into this category include those who perform within the normal range on standard neuropsychological tests, and people over age 65 who already have a clear AD diagnosis. In the former case, researchers do not know enough to tell individuals with any certainty how and when their cognition might slip; in the latter case, amyloid imaging would contribute little to their clinical workup, the committee argued.

“Physicians do not need amyloid scans for typical, garden-variety late-onset AD,” said William Klunk, University of Pittsburgh, Pennsylvania, who co-discovered PIB, sees patients, and helped advise the committee. “They need it in confusing cases, in mild cognitive impairment, and in other forms of atypical young-onset cases.”

One patient group left off the eligibility list may benefit from scans down the road, said Salloway. To researchers’ surprise, a third of ApoE4 non-carriers diagnosed clinically with mild AD turned out to be amyloid-negative in recent Phase 3 trials (see ARF related news story and ARF news story). “They may not have significant amyloid burden and may not have Alzheimer’s,” Salloway told Alzforum. At some point, it may make sense to use ApoE4 as a screening tool to decide whom to target for amyloid imaging; in other words, clarify the clinical diagnosis of mild AD in non-carriers with a scan, Salloway said.

The committee cautioned that amyloid imaging, in its current form, cannot determine the severity of a person’s dementia. It cannot be used to stage dementia in people who carry familial AD mutations, as some had suggested. The committee advises against imaging as a substitute for genetic testing when familial AD is suspected. Doctors should never prescribe a scan based solely on a family history of AD or the presence of AD risk factors, such as the ApoE4 allele, when there are no symptoms. Amyloid PET is also inappropriate for non-medical uses, such as in insurance, legal, or employment decisions.

The committee recommended that only physicians with expertise in diagnosing and treating memory disorders should order amyloid PET scans. Scan results should form part of a broader diagnostic workup—not serve as stand-alone diagnoses. AIT also advised that results be disclosed to the patient with a thorough explanation of their meaning.

One audience member wondered if primary care physicians should order the test, since a positive result could help them refer people to dementia care specialists. Christopher Rowe, University of Melbourne, Australia, who chaired this session and is part of the AIT, pointed out that a study led by Gil Rabinovici at the University of California, San Francisco, suggests scan results have little impact on patient care, arguing against broad, expensive scanning efforts at this time (see below). Additionally, Rabinovici said that widespread use of amyloid imaging could cause more harm than good if interpreted by physicians who do not understand the nuances.

These guidelines may influence not only clinicians, but also health insurers, who typically follow the Centers for Medicare & Medicaid Services’ (CMS) rules for reimbursing Medicare and Medicaid patients. A CMS panel will meet 30 January in Baltimore, Maryland, to review whether amyloid imaging improves care of dementia patients (see ARF related news story; MEDCAC meeting). The panel will later advise the CMS on reimbursement. Currently, CMS explicitly excludes coverage of all new positron emission tomography (PET) radiotracers. “The key issue is whether amyloid status changes patient management,” Johnson said. In the absence of a treatment, some see that as unlikely. “That’s the biggest threshold to cross for this technology,” said Johnson.

What does the field know about this question? Research on it is only just beginning. While scan results could, in theory, improve patient care even in the absence of a treatment, there are few data to support this idea. At HAI, Andrew Siderowf of Avid Pharmaceuticals, the maker of Amyvid, presented data published this month on one such study (see Grundman et al., 2013). It examined whether amyloid imaging changed the diagnosis, the physician’s confidence in the diagnosis, planned use of other tests, or patient treatment. The study, conducted at 19 clinical centers, included 229 people with dementia or cognitive decline whose physicians were less than 85 percent certain about their diagnoses.

Before and after amyloid imaging, physicians provided a diagnosis, an estimate of their confidence in the decision, and hypothetical plans for future diagnostic evaluation and management (the study did not track actual patient outcomes, but an upcoming Avid Phase 4 trial will). As might perhaps be expected from a study funded by the tracer’s manufacturer, Siderowf reported that the scan results did indeed influence those decisions. About half the clinicians changed their diagnosis after receiving amyloid PET results, and their diagnostic confidence rose 22 percent. For 87 percent of patients, physicians planned at least one disease management change, for instance, stopping or starting a cognitive enhancing or psychiatric medication. For patients without a complete diagnostic workup at study entry, plans for brain structural imaging, neuropsychological testing, and fluorodeoxyglucose (FDG) PET were shelved after the amyloid PET scan about 52, 65, and 91 percent of the time, respectively.

The study did not address why those other tests were abandoned, Siderowf said. “One possibility is that physicians may have decided to watch and wait rather than perform additional testing that might not provide any useful information,” he told Alzforum in an e-mail.

If this were to happen broadly, costly amyloid scans might marginalize and over time replace other means of assessment. Indeed, at least one audience member at HAI expressed concern about the observed drop in AD diagnostic tests. “These results suggest that physicians may be overinterpreting amyloid scan results as providing a definitive diagnosis, whereas they should be treated as just one piece of the diagnostic puzzle,” said Rabinovici. “There is no evidence to suggest that these scans should substitute for the current standard of care, which includes cognitive testing and structural imaging, particularly in complex cases.” Siderowf agreed. “It is important to note that Amyvid is neither a screener for asymptomatic patients nor a stand-alone diagnostic for AD—it should be used as an adjunct to other diagnostic evaluations,” he told Alzforum.

Rabinovici presented his own study on the clinical impact of amyloid scans. He looked back at the records of 140 dementia patients from the UCSF Memory and Aging Center for whom physicians had incorporated results from FDG and Pittsburgh compound B (PIB) PET imaging. He and colleagues wanted to know if the diagnosis had changed from an Aβ to a non-Aβ disorder or vice versa, or if patients started or stopped treatment with memantine or cholinesterase inhibitors based on an amyloid scan.

Less than 10 percent of diagnoses changed. Those that did tended to side with PIB scans more than the FDG scan if the two were at odds. Though physicians altered AD symptomatic therapy in 36 percent of patients after PET scans, these adjustments did not associate with PIB or FDG results, Rabinovici said.

Siderowf's and Rabinovici's data paint different pictures of the outcome after amyloid scanning. It is difficult to directly compare these two studies because of the difference in design, noted Johnson. For one thing, the Avid study details what physicians intended to do, rather than measures they actually took, as did Rabinovici’s study. “There might be important differences between intended and observed behavior,” Johnson said. Avid’s is a multisite study. It incorporated clinicians from a wide variety of settings and backgrounds, as opposed to the single-site UCSF study, Salloway pointed out. Given that only a small proportion of patients can attend such highly specialized centers, the results of the Avid study may be more generalizable to the community, he told Alzforum. Salloway was a contributing physician in Avid’s work.

Study differences aside, the fact that physicians used scans to refine their diagnoses and modify patient treatment plans is “encouraging, and what you’d expect for a useful biomarker,” Klunk said. As these are just the first studies that look into how amyloid imaging plays out in clinical practice, neither represent the final word on its impact, he told Alzforum.—Gwyneth Dickey Zakaib

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References

News Citations

1. FDA Approves Amyvid for Clinical Use 9 Apr 2012
2. Amyloid Imaging Task Force to Work Out Technology's Use 13 Jun 2012
3. The Solanezumab Benefit: Oh, So Small, But Probably Real 9 Oct 2012
4. Bapineuzumab Phase 3: Target Engagement, But No Benefit 12 Sep 2012

Paper Citations

1. Grundman M, Pontecorvo MJ, Salloway SP, Doraiswamy PM, Fleisher AS, Sadowsky CH, Nair AK, Siderowf A, Lu M, Arora AK, Agbulos A, Flitter ML, Krautkramer MJ, Sarsour K, Skovronsky DM, Mintun MA, . Potential impact of amyloid imaging on diagnosis and intended management in patients with progressive cognitive decline. Alzheimer Dis Assoc Disord. 2013 Jan;27(1):4-15. PubMed.

Other Citations

1. ARF related news story

External Citations

1. Alzheimer's & Dementia
2. Journal of Nuclear Medicine
3. MEDCAC meeting
4. Phase 4 trial

Further Reading

Papers

1. Grimmer T, Wutz C, Drzezga A, Förster S, Förstl H, Ortner M, Perneczky R, Kurz A. The usefulness of amyloid imaging in predicting the clinical outcome after two years in subjects with mild cognitive impairment. Curr Alzheimer Res. 2012 Oct 3; PubMed.

News

1. Amyloid Imaging Task Force to Work Out Technology's Use 13 Jun 2012
2. Coming to a City Near You: Tracer to Picture Brain Amyloid 13 Jun 2012
3. Who Will Pay for New Amyloid Scans? The Lobbying Has Begun 29 Aug 2012
4. Insurance Coverage of AD Diagnostics? Not Without Better Data 15 Dec 2012
5. Love a Good Fight? Check Out Brouhaha Over Amyloid Imaging 2 Feb 2012
6. FDA Approves Amyvid for Clinical Use 9 Apr 2012
7. The Solanezumab Benefit: Oh, So Small, But Probably Real 9 Oct 2012
8. Bapineuzumab Phase 3: Target Engagement, But No Benefit 12 Sep 2012