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FDA Panel Recommends New Imaging Agent for AD Detection

Talan, Jamie

doi: 10.1097/01.NT.0000394976.61485.ab
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A new PET agent detected amyloid-beta plaque in vivo in end-stage patients, which was consistent with their pathology reports postmortem. But experts said more research needs to be done to test the specificity and sensitivity of the agent for early detection of Alzheimer disease.

An FDA advisory panel voted unanimously in favor of approving a new PET radiotracer agent — florbetapir — as an imaging marker for amyloid beta (Abeta). The compound, florbetapir, was able to label Abeta in living people and the PET scans correlated with pathology findings at death.

But experts not involved with the Jan. 19 paper in The Journal of the American Medical Association (JAMA) on which the panel recommendation was based said that although the results were encouraging, the study did not yet provide sufficient data to support the agent's use for early detection of Alzheimer disease (AD).

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Clinicians reached out to hospice, long-term care, and community health facilities to identify patients in the final months of life willing to undergo a PET scan and an autopsy. The florbetapir-PET imaging was performed on average about 99 days before death in 29 people who were part of the primary analysis cohort — a larger group of 152 end-of-life patients who had had brief physical, neurological and cognitive evaluation to assess memory, language and thinking abilities. Before this study, six others were tested to establish the protocol.

Fifteen of the 29 older volunteers (51.7 percent) met pathological criteria for AD. Three board certified nuclear medicine physicians independently read the PET scans and made the diagnosis based on the burden of amyloid plaque deposition. Following the pathology report from the autopsy, the results from the PET scan and the postmortem diagnosis were compared. There was agreement between the PET and autopsy results 96 percent of the time.

The findings provide evidence that Abeta pathology can be assessed during life.

In an attempt to determine the specificity of the scan, the investigators also studied 74 younger adults (between 18 and 50) and an independent analysis (again by three nuclear medicine physicians) was conducted to see whether any of clinicians thought that they saw signs of Abeta deposition. These physicians were not part of the study.

According to the JAMA study, the scans from these younger brains were mixed randomly with 40 images from scans taken from those older people who were autopsied. None of the scans from the younger brains showed any evidence of Abeta deposition.

According to study investigator Eric Reiman, MD, executive director of the Banner Alzheimer's Institute and director of the Arizona Alzheimer's Consortium, imaging amyloid deposition is already playing critical roles in the research setting and it promises to help in the clinical evaluation of patients.

Before this technique could be approved in the clinical setting, the FDA advisory committee had previously indicated the need to show that it met the “standard of truth:” that is, that PET measurements in living people corresponded closely to a pathologists measurements in the same people after they died.

William Klunk MD, PhD, professor of psychiatry and neurology at the University of Pittsburgh, developed the first Abeta imaging agent, Pittsburgh Compound B, in 2004. It has a very short half-life — 20 minutes — and thus it limits its potential outside of a clinical trial. Dr. Reiman noted that the newer agent has a longer half-life (110 minutes), making it possible for use in a wider PET scanner catchment area.

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The results of this study are impressive, experts said. “This finding may have major relevance for the diagnosis of Alzheimer disease and monitoring of brain amyloid pathology,” said Monique M. B. Breteler, MD, PhD, head of the Neuroepidemiology Section of the Department of Epidemiology at Erasmus Medical Center in Rotterdam, The Netherlands. Dr. Breteler, who wrote an accompanying editorial in JAMA, called the design of the study “elegant,” but, she said, the present “study falls short in evaluating the sensitivity and specificity of florbetapir imaging” for AD. The biomarker “must be validated in the population and clinical setting for which the biomarker is intended.”

She noted that the participants did not come from a random sampling of asymptomatic people, but were instead ”terminally ill persons who, for the most part, had advanced dementia or nondementia disorders, mostly cancer,” adding, the “reported agreement of 96 percent between florbetapir-PET and the postmortem pathologic diagnosis is likely inflated because of the selection of participants in the study.”

Members of the FDA advisory panel were also impressed by the study but said that they wanted the team to test whether they can train one individual to read the scan and come up with the right diagnosis. They noted that the study depended on evaluations of three clinicians. Any imaging technology must be able to confirm the presence of amyloid deposits in the brain and rule out images that do not have such deposition, they said.

The problem with imaging amyloid in the brains of elderly people is that 30 percent of people over 75 years old have amyloid plaques and no signs of dementia, the study authors noted. That means a PET scan to measure amyloid might not stand alone as a way to diagnose Alzheimer's but it can be a way to rule out the disease and guide the clinician to other possible causes of dementia.

The AD field knows a lot about the disease and one thing has become clear, said John C. Morris, MD, director of the Alzheimer's Disease Research Center at Washington University School of Medicine in St. Louis, MO. “By the time symptoms develop, a single approach won't do. If the amyloid hypothesis is correct, the time to initiate treatment is prior to the development of the pathological cascade and the resulting symptoms. And that is the promise of these biomarkers.”

The Jan. 19 JAMA study, which was led by Christopher M. Clark, MD, associate director of the University of Pennsylvania Alzheimer's Disease Center and director of the Memory Disorders Clinic. Dr. Clark is also employed by and has stock options with Avid Radiopharmaceuticals, which sponsored the study.

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Clark CM, Schneider JA, Skovronsky DM, et al for the AV45-A07 Study Group. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011;305(3):275–283.
    Breteler MMB. Editorial: Mapping out biomarkers for Alzheimer disease. JAMA 2011;305: 304–305.
      ©2011 American Academy of Neurology