Autopsy Confirms Negative Florbetaben Scan Excludes Amyloid

Susan Jeffrey

April 30, 2014

PHILADELPHIA — A new study shows that positron emission tomography (PET) using florbetaben (Neuraceq, Piramal Imaging) can reliably exclude the presence of amyloid in the brain of patients with dementia.

In the largest such study to date, researchers found a high negative predictive value of a negative florbetaben scan, showing a close correlation between uptake of the tracer and amyloid deposition in the brains of patients at autopsy.

"We can absolutely say with over 95% certainty that if the scan is negative, the pathology is negative," lead author Marwan Sabbagh, MD, director of the Banner Sun Health Research Institute and Institute Research Professor of Neurology at the University of Arizona College of Medicine, Phoenix, told Medscape Medical News.

"A negative scan should encourage the physician to search for other causes of cognitive decline and tailor available treatment options," the authors conclude.

The findings were presented here at the American Academy of Neurology (AAN) 66th Annual Meeting.

Dr. Marwan Sabbagh

Neuritic Plaque Density

The US Food and Drug Administration (FDA) approved florbetaben F18 injection in March of this year, indicated for PET imaging of the brain to estimate β-amyloid neuritic plaque density in adults with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive decline. It is the third amyloid PET tracer to be approved; the others are florbetapir (Amyvid, Eli Lilly and Co) and flutemetamol (Vizamyl, GE Healthcare), were approved by the FDA in 2012 and 2013, respectively.

Negative and positive florbetaben scans

At this time, the Centers for Medicare & Medicaid Services will cover β-amyloid PET for patients only under Coverage with Evidence Development programs that aim to assess the utility of these scans to improve patient outcomes or advance patient treatment options, a decision that has disappointed some in the AD community.

In this study, Dr. Sabbagh and colleagues in 5 countries (Japan, Germany, France, Australia, and the United States) aimed to assess the diagnostic efficacy and negative predictive value of florbetaben in a large cohort of participants with advanced disease, all of whom underwent florbetaben PET imaging as well as MRI before their death.

This analysis looked at scans from 74 patients who died and underwent brain autopsy with final neuropathologic diagnosis. Of these, the clinical diagnosis was 57 patients with AD, 3 patients with Lewy body dementia, 8 volunteers without dementia, and 6 patients with other dementias. The scan assessment was then compared with the presence or absence of neuritic β-amyloid plaques determined according to Consortium for Establishing a Registry for Alzheimer's Disease criteria.

"In a previously reported interim analysis of 31 patients a regional analysis was performed. This study represents further follow-up of a large cohort analyzed on the subject level. The study includes both regional and subject-level analysis, and the subject level is reported here," Dr. Sabbagh noted.

Table. Histopathologic Findings by Clinical Diagnosis

Diagnosis (n) β-Amyloid Present (n) No β-Amyloid (n)
AD (57) 44 13
Lewy body dementia (3) 1 2
Other dementia (6) 1 5
Volunteers without dementia (8) 1 7

 

They report that florbetaben scans were correctly read as positive in 46 of 47 participants with β-amyloid for a sensitivity of 98%. Scans from 24 of 27 participants without β-amyloid were correctly read as negative, for a specificity of 89%. Twenty-four of 25 scans read as negative were correctly assessed, they note, for a negative predictive value of 96%.

The presence of other neuropathologies, such as Parkinson's disease, did not affect the assessment of scans, the authors note.

One puzzling finding is that in the group with a diagnosis of AD who came to autopsy, 13 were not positive for β-amyloid, Dr. Sabbagh notes. Although that may be beyond the scope of this paper, "and a discussion for a different day," he said, " what I can say is that if it was negative on the scan, it was negative on the autopsy."

"Florbetaben imaging can reliably exclude amyloid pathology as demonstrated by the high negative predictive value," they conclude. "It is a valuable adjunct for the exclusion of Alzheimer's disease or differential diagnosis of dementia."

"The label we've been given is very focused on the negative predictive value," said Andrew W. Stephens, MD, PhD, chief medical officer of Piramal Imaging. "If you have a negative scan, it means with a very high likelihood that you do not have amyloid in your brain. That's the sine qua non of Alzheimer's disease as we're defining it, and so this is not Alzheimer's in the traditional sense."

Dr. Andrew W. Stephens

True Link

At a press conference here, Natalia Rost, MD, MPH, director of the Acute Stroke Service at Massachusetts General Hospital, associate professor of neurology at Harvard Medical School, Boston, Massachusetts, and vice-chair of the AAN Science Committee, highlighted this paper as 1 of the top 3 papers of interest being presented.

"This study is a true link between the neuroimaging and histopathological markers of Alzheimer's disease," Dr. Rost said. "The reason this study is important is they've been able to correlate the findings from florbetaben PET scans done prior to their death to the histopathology of the patients enrolled in this study."

The high sensitivity and specificity see in these results mean that it may be possible to rule out AD pathology in these patients early on.

"This is good for clinicians making decisions with regard to further work-up strategies, rather than just relying on a common diagnosis of Alzheimer's disease, and also allow us to stratify patients for future clinical trials," she said.

The study was supported by Piramal Imaging. Dr. Sabbagh reports he has received personal compensation for activities with AmeriSciences, Pfizer, Eisai, Lilly, Avid, BMS, and Allon; personal compensation in an editorial capacity for Cognivite Complete and Wiley; and research support from Avid, Baxter, BMS, Celgene, Eisai, Elan, Eli Lilly, GE, Genentech, Janssen/Wyeth, Pfizer, and Piramal Imaging. Disclosures for coauthors are available with the abstract.

American Academy of Neurology (AAN) 66th Annual Meeting. Emerging Science Abstract 003. Presented April 30, 2014.

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