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Technology Evaluation
Center (TEC)


Beta Amyloid Imaging with Positron Emission Tomography (PET) for Evaluation of Suspected Alzheimer’s Disease or Other Causes of Cognitive Decline

Executive Summary

Background

Alzheimer’s disease (AD) is the most common cause of dementia in the U.S., and is responsible for a considerable and increasing burden of morbidity and mortality. Currently an estimated 5.3 million individuals in the U.S. suffer from AD; this prevalence is expected to increase to 11–16 million by 2050. The most recent classification of AD in clinical settings includes “Possible AD dementia” or “Probable AD dementia.” The category of “Pathophysiologically proved AD dementia” requires neuropathologic examination documenting the presence of extracellular beta amyloid plaques and neurofibrillary tangles in the cerebral cortex. Probable and possible AD are primarily clinical diagnoses. An estimated 10% to 20% of individuals diagnosed with clinical AD do not meet the histopathologic criteria for AD on autopsy, which is the reference standard, and thus the clinical diagnosis was incorrect. The presence of beta amyloid deposition in the brain is a necessary but not sufficient condition for AD. Conversely, the absence of beta amyloid deposition rules out AD at that time. The precise role of beta amyloid in AD initiation and progression has long been a subject for research and debate and continues to be so. Treatment with cholinesterase inhibitors or memantine for people with mild to severe dementia due to AD produces statistically significant, but clinically marginal, improvement at 6 months and 1 year in measures of cognitive function when compared to placebo, despite higher rates of study discontinuation and adverse effects. These medications may also be used in patients with other types of dementia.

Objective

To determine whether evaluating patients with suspected Alzheimer’s disease (AD) or other causes of cognitive decline using beta amyloid imaging by positron emission tomography (PET) results in improved health outcomes compared to no testing.

Search Strategy

A MEDLINE® (via PubMed) literature search using the term “florbetapir” performed in January 2013 identified 53 publications. EMBASE was also searched. Bibliographies of included studies were examined for additional citations. Selective searches were conducted for the background sections of the report on, for example, treatments for AD.

Selection Criteria

  • Use of florbetapir F18 with PET imaging to detect beta amyloid deposition in the human brain. Other beta amyloid radiotracers were not included because they are not approved by the U.S. Food and Drug Administration (FDA) (e.g., 18F-florbetaben, 18F-flutemetamol).
  • Study populations include subjects with possible or probable AD, mild cognitive impairment (MCI), or other cognitive decline.
  • Reference standard is clinical diagnosis and/or postmortem histopathologic findings.

Main Results

Evidence on technical performance is mainly from a study by Clark et al. submitted for FDA approval. This was a Phase III multicenter trial with an autopsy cohort (n=29) and a young, cognitively intact cohort (n=47). The autopsy cohort included 9 subjects (31%) who were not cognitively impaired, 2 (7%) who were mildly impaired, 13 (45%) with a clinical diagnosis of AD, and 5 (17%) with a clinical diagnosis of a non-AD dementia. Histopathologic amyloid burden was assessed in all patients, with 52% meeting pathologic criteria for AD. A significant correlation of 0.78 was found between amyloid burden in the brain measured by florbetapir F18 and histopathology. Of 15 subjects who met pathologic criteria for AD, 14 had positive florbetapir scans (sensitivity of 93%). In the specificity cohort to evaluate false positives, the primary endpoint was the exclusion of amyloid in 47 young subjects who were negative for the apolipoprotein E ε4 (APOE4) allele, randomly interspersed with PET scans of 40 subjects in the autopsy cohort. The study achieved specificity of 100% in this cohort, although the young controls who formed a majority of the specificity cohort are outside of the intended use population.

Reproducibility of the readings was assessed by 3 trained readers blinded to the clinical information. Using a binary scale (positive or negative for amyloid), sensitivity ranged from 55% to 90% for the 3 readers. Subsequent reanalysis for publication used the majority rating of 3 nuclear medicine physicians as the primary outcome variable, resulting in 96% agreement between florbetapir- PET images and histopathologic results in the 29 subjects in the primary analysis cohort.

A strength of this study is the comparison of florbetapir F18 imaging with the reference standard of post-mortem histopathology. Limitations include the small sample size, a majority rating for assessing diagnostic accuracy, and only 2 patients in the mildly impaired category, which is the population in whom the test is most likely to be used. There is evidence for inter-observer variability in reading the test; using a majority of 2/3 readers leads to a high agreement with histopathology. Further high-quality studies from patient populations representing those presenting in clinical care are needed to better define the diagnostic performance of this test.

A small independent study (Avid Radiopharmaceuticals only provided the Amyvid) reported the diagnostic performance of florbetapir F18 PET in a clinical setting. Included were 13 subjects with AD, 12 with MCI, and 21 older unimpaired controls. Agreement in visual analysis between the 2 readers had a kappa value of 0.71. Comparing visual assessment with the initial clinical diagnosis, 11 of 13 AD patients (85%), 6 subjects with MCI (50%) and 13 of 21 control subjects (60%) had positive scans, resulting in a sensitivity of 84.6% and a specificity of 38.1% for discriminating AD patients from control subjects. Although study conclusions are limited by the small number of subjects and the use of clinical diagnosis as a reference standard, these results suggest a high number of false positives with visual image assessment. In addition, quantitative analysis could not differentiate subjects with MCI from unimpaired controls.

There is no direct evidence for clinical utility of beta amyloid imaging. Additional research is needed on the sensitivity and specificity of beta amyloid testing. It is not possible to link an indirect chain with existing evidence to convincingly argue health outcomes are improved. Furthermore, several factors make it difficult to ascertain the potential net benefit associated with use of florbetapir F18 PET:

  • The limited effectiveness of pharmacologic treatments for AD, as well as for other types of dementia that may be difficult to distinguish from AD
  • Pharmacologic treatment efficacy has been demonstrated in patients with clinically diagnosed AD, which may or may not be equivalent to patients with positive florbetapir F18 results.
  • The generally modest adverse effects of medications used for AD, with some evidence of effectiveness in non-AD dementia, so that these medications are used widely in patients with dementia
  • The coexistence of AD with other types of dementia

Author’s Conclusions and Comment

In general, evidence of a health benefit or clinical utility from testing requires demonstration of:

  • incremental improvement in diagnostic or prognostic accuracy over current practice and
  • that incremental improvements lead to improved health outcomes (e.g., by informing clinical management decisions), and
  • that these outcomes may be obtained (i.e., are generalizable) outside of the investigational setting.

The use of florbetapir F18 PET in individuals with suspected AD, other causes of dementia, or cognitive decline does meet any of these criteria. Studies have shown that florbetapir F18 PET results correlate with histopathologic findings at autopsy. This finding is important. Studies have also suggested that florbetapir F18 PET has some ability to differentiate between cognitively normal adults and patients with AD. However, the studies are limited by small sample sizes, differences in determining outcomes (e.g., qualitative versus quantitative, unknown impact of training for physicians inexperienced with this modality), and the lack of evidence obtained from populations encountered in clinical practice. No information is available on the impact of this test on clinical outcomes, and few data are available on whether it can accurately identify patients with MCI who will develop AD.

Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel (MAP) made the following judgments about whether beta amyloid imaging with positron emission tomography (PET) meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria to evaluate suspected Alzheimer’s disease (AD) and other causes of cognitive decline.

1. The technology must have final approval from the appropriate governmental regulatory bodies.

In 2012, the U.S. Food and Drug Administration (FDA) approved the use of one beta amyloid radioactive diagnostic agent, florbetapir F18 (Amyvid™, Avid Radiopharmaceuticals, Inc., a subsidiary of Eli Lilly), for use with PET. Florbetapir F18 is indicated to estimate beta-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline, as an adjunct to other diagnostic evaluations.

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

The available evidence is insufficient to permit conclusions concerning the impact of beta amyloid PET imaging with florbetapir F18 on health outcomes. The evidence to date focuses solely on the correlation between the results of beta amyloid PET imaging and other indicators of cognitive decline, clinical diagnoses, and histopathologic results. Studies are needed to define the accuracy of beta amyloid imaging according to age (since beta amyloid deposition increases with age in cognitively normal individuals). Further evidence is also needed on the link between the test results and improving health outcomes.

3. The technology must improve the net health outcome.

Because evidence is insufficient to permit conclusions on the effect of beta amyloid PET imaging on health outcomes, any improvement cannot be established.

4. The technology must be as beneficial as any established alternatives.

Comparative benefit cannot be established lacking sufficient evidence.

5. The improvement must be attainable outside the investigational setting.

Improved health outcomes following beta amyloid PET imaging have not been demonstrated in the investigational setting.

Based on the above, beta amyloid imaging with positron emission tomography (PET) to evaluate suspected Alzheimer’s disease (AD) and other causes of cognitive decline does not meet the TEC criteria.

Full Study

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AD; allele; Alzheimer’s; Alzheimers; amyloid; Amyvid; APOe; apolipoprotein; Avid; AZD4694; cholinesterase; CJD; Clinical Dementia Rating; cognitive; compound B; Creutzfeldt-Jakob Disease; deficit; degeneration; dementia; Eli Lilly; encephalopathy; epsilon; F18; FDDNP; florbetaben; florbetapir; fluorine 18; flutemetamol; frontotemporal dementia; Huntington’s disease; PET; Korsakoff syndrome; language; Lewy body; memantine ; National Institute on Aging-Alzheimer’s Association; neurofibrillary; normal pressure hydrocephalus ; PET; PiB; Pick’s disease; Pittsburgh; positron emission tomography; postmortem; presenilin; PSEN; synuclein; tangles; thiamine; vascular; visuospatial; Wernicke;