Coverage Policy Manual
Policy #: 2012026
Category: Radiology
Initiated: June 2012
Last Review: March 2024
  PET Scan for Alzheimer's Disease, Dementia, or Cognitive Impairment Using Beta Amyloid Imaging

Description:
Alzheimer disease (AD) is a fatal neurodegenerative disease that causes progressive loss in memory, language, and thinking, with the eventual loss of ability to perform social and functional activities in daily life. Survival after a diagnosis of dementia due to AD generally ranges between 4 and 8 years; however, life expectancy can be influenced by other factors, such as comorbid medical conditions. It is estimated that 6.2 million Americans aged 65 and older are currently living with AD dementia, and the number is projected to reach over 12 million by 2050 (Alzheimer facts and figures, 2021).
 
The pathologic hallmarks of AD are extracellular deposits of amyloid beta, referred to as amyloid plaques, and intracellular aggregates of hyperphosphorylated tau in the form of neurofibrillary tangles. There are different forms of amyloid such as plaques, oligomers, and monomers, and the roles of these different forms and how specifically they are pathophysiologically associated with AD is not well understood. Generally referred to as “amyloid hypothesis”, it is believed that aggregation of amyloid beta oligomers in the brain leads to amyloid plaques and is thought to be the primary driver of the disease process. These changes in the brain result in widespread neurodegeneration and cell death, and ultimately cause the clinical signs and symptoms of dementia (Alzheimer’s Association, 2021; Roberts, 2018).
 
Because clinical diagnosis can be difficult, particularly early in the course of the disease or with atypical dementia, there has been considerable interest in developing biomarkers for AD that can be imaged through positron emission tomography (PET). These biomarkers include amyloid beta plaque and glucose metabolism in the brain. PET images biochemical and physiologic functions by measuring concentrations of radioactive chemicals that have been partially metabolized in a particular region of the body. Radiopharmaceuticals used for PET imaging may be generated in a cyclotron or nuclear generator and introduced into the body by intravenous injection.
 
Demonstration of amyloid beta plaque is a requirement for the diagnosis of definite AD, but may also be present in individuals without dementia, in patients with mild or subjective cognitive impairment who may or may not progress to dementia, and in patients with other types of dementia. Conversely, it may be absent in a substantial proportion of patients with clinical features of AD (Vallabhajosula, 2011; Ossenkoppele, 2015; Jansen, 2015).
 
PET imaging in patients with mild cognitive impairment (MCI) or dementia is intended to provide a more accurate diagnosis earlier in the disease course than clinical diagnosis alone, resulting in earlier, appropriately targeted treatment and other management approaches.
 
 
Regulatory Status
 
PET radiopharmaceuticals have been evaluated and approved as drugs by the FDA for use as diagnostic imaging agents. These radiopharmaceuticals are approved for specific conditions.
 
Amyvid™, Vizamyl™, and Neuraceq™ are approved by the FDA "for PET imaging of the brain to estimate amyloid beta neuritic plaque density in adult patients with cognitive impairment who are being evaluated for AD and other causes of cognitive decline" (Eli Lilly and Company, 2013; GE Healthcare, 2016; Piramal Imaging, 2014).
 
The prescribing information for all 3 agents used for amyloid beta imaging states:
    • The objective of Aβ image interpretation is to estimate beta-amyloid neuritic plaque density in brain gray matter, not to make a clinical diagnosis.  
    • A positive Aβ scan does not establish the diagnosis of AD or other cognitive disorder.  
    • A negative Aβ scan “indicates sparse to no neuritic plaques, and is inconsistent with a neuropathologic diagnosis of AD at the time of image acquisition; a negative scan result reduces the likelihood that a patient’s cognitive impairment is due to AD.”
    • Florbetapir, florbetaben, and flutemetamol are not intended for use in “predicting development of dementia or other neurological condition” or for “monitoring responses to therapies.”
 
Radioactive Tracers Approved by the FDA for Amyloid Beta PET Imaging in Patents with Cognitive Impairment
    • florbetapir F18 (Amyvid™), manufactured by Avid Radiopharmaceuticals (subsidiary of Eli Lilly) (NDA 202008) was approved in 2012
    • flutemetamol F18 (Vizamyl™), manufactured by GE Healthcare, (NDA 203137) was approved in 2013
    • florbetaben F18 (Neuraceq™), manufactured by  Piramal Life Sciences, (NDA 204677) was approved in 2014
 
Coding
At this time, there is no code specific to florebetapir. HCPCS code A4641 could be used. The PET scan would be reported using the CPT codes for PET or PET/CT scanning (i.e., 78811 or 78814).
 
Effective July 2016 there are new HCPCS for Flutemetamol and Florbetaben F18.
Q9982 - Flutemetamol F18, diagnostic, per study dose, up to 5 millicuries
Q9983 - Florbetaben F18, diagnostic, per study dose, up to 8.1 millicuries
 
Effective in 2013, there is a HCPCS code specific to florbetapir:
A9586: Florbetapir F18, diagnostic, per study dose, up to 10 millicuries
 
Prior to 2013, there was no code specific to florbetapir. HCPCS code A4641 would have been used. The PET scan would be reported using the CPT codes for PET or PET/CT scanning (i.e., 78811 or 78814).
 
Related policies:
2009009_Biochemical Markers, Alzheimer’s Disease
1998137_Genetic Test: Alzheimer’s Disease
2004047_PET Scan, Positron Emission Tomography, for Alzheimer's
2007001_Magnetic Resonance Imaging (MRI), Functional

Policy/
Coverage:
Effective July 2022
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Amyloid beta imaging with positron emission tomography (PET) to predict conversion to Alzheimer disease does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, amyloid beta imaging with positron emission tomography (PET) to predict conversion to Alzheimer disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Amyloid beta imaging with PET as an adjunct to clinical diagnosis in patients with dementia does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, amyloid beta imaging with PET as an adjunct to clinical diagnosis in patients with dementia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Amyloid beta imaging with PET to select patients with mild cognitive impairment or mild dementia due to Alzheimer disease for amyloid beta targeting therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, amyloid beta imaging with PET to select patients with mild cognitive impairment or mild dementia due to Alzheimer disease for amyloid beta targeting therapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Amyloid beta imaging with PET to evaluate patients with mild cognitive impairment or mild dementia due to Alzheimer disease for continuation of amyloid beta targeting therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, amyloid beta imaging with PET to evaluate patients with mild cognitive impairment or mild dementia due to Alzheimer disease for continuation of amyloid beta targeting therapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
All other uses of amyloid beta imaging with PET do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, all other uses of amyloid beta imaging with PET are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Radiopharmaceuticals used for Amyloid beta imaging with PET to predict conversion to Alzheimer disease, as an adjunct to clinical diagnosis in patients with dementia, to evaluate patients with mild cognitive impairment or mild dementia due to Alzheimer disease for continuation of amyloid beta targeting therapy, and all other uses of amyloid beta imaging with PET do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, radiopharmaceuticals used for Amyloid beta imaging with PET to predict conversion to Alzheimer disease, as an adjunct to clinical diagnosis in patients with dementia, to evaluate patients with mild cognitive impairment or mild dementia due to Alzheimer disease for continuation of amyloid beta targeting therapy, and all other uses of amyloid beta imaging with PET are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective February 2022 through June 2022
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Amyloid beta imaging with positron emission tomography (PET) to predict conversion to Alzheimer disease does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, amyloid beta imaging with positron emission tomography (PET) to predict conversion to Alzheimer disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Amyloid beta imaging with PET as an adjunct to clinical diagnosis in patients with dementia does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, amyloid beta imaging with PET as an adjunct to clinical diagnosis in patients with dementia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Amyloid beta imaging with PET to select patients with mild cognitive impairment or mild dementia due to Alzheimer disease for amyloid beta targeting therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, amyloid beta imaging with PET to select patients with mild cognitive impairment or mild dementia due to Alzheimer disease for amyloid beta targeting therapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Amyloid beta imaging with PET to evaluate patients with mild cognitive impairment or mild dementia due to Alzheimer disease for continuation of amyloid beta targeting therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, amyloid beta imaging with PET to evaluate patients with mild cognitive impairment or mild dementia due to Alzheimer disease for continuation of amyloid beta targeting therapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
All other uses of amyloid beta imaging with PET do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, all other uses of amyloid beta imaging with PET are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to February 2022
 
PET imaging with beta amyloid for the evaluation of Alzheimer’s disease or other cognitive impairment does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  Florbetapir is still being studied in ongoing trials.  PET imaging with Florbetapir is not specific for Alzheimer's and there has been no medical literature reporting improved health outcomes as a result of this testing.
 
For contracts without primary coverage criteria PET imaging with beta amyloid for the evaluation of Alzheimer’s disease or other cognitive impairment is considered investigational.  Investigational services are exclusions in the member Summary Plan Description.
 
 

Rationale:
Literature Review
Technical Performance
Evidence on technical performance of this test should demonstrate that the test measures what it is intended to, i.e., beta-amyloid plaque. The best evidence on this would be direct comparison with a gold standard test for measuring amyloid plaque, which is histopathologic examination of tissue. Other important measures of technical performance are the reliability of testing, including both test-retest reliability and interobserver reliability in reading test results.
 
Data on technical performance of the test was included in an FDA-regulated study, which was published in 2011 (Clark).  This study was a phase III multicenter trial with 2 separate cohorts. These cohorts were an autopsy cohort and a young, cognitively intact cohort. The autopsy cohort was drawn from 152 subjects who had a projected life expectancy of 6 months or less. Thirty-five individuals passed away and were autopsied within 12 months of PET imaging; 29 were included in the primary efficacy analysis. This cohort was composed of 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.
 
All patients had direct measurement of amyloid burden by histopathologic examination, and 52% met the pathologic criteria for AD.  A significant correlation of 0.78 was found between amyloid burden in the brain measured by Amyvid and the gold standard of histopathology, however, there was not an exact match between the 2 measures. The correlation between quantitative whole-brain florbetapir image scores and post-mortem silver stain was 0.71.  In the young controls (specificity cohort to evaluate false positives), the primary efficacy 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 it is noted that the young controls are outside of the intended use population.
 
Reproducibility of the readings was assessed using 3 trained readers who were blinded to the clinical information.  Using a binary scale (positive or negative for amyloid), sensitivity ranged from 55% to 90% for the 3 readers, and in 24%- 45% of the images (depending on the sample) at least 1 reader would have had a different interpretation of amyloid status from the other readers (FDA 2011). Subsequent reanalysis for publication used the majority rating of three nuclear medicine physicians as the primary outcome variable, resulting in 96% agreement between florbetapir-PET images and histopathological results in the 29 subjects in the primary analysis cohort (Clark 2011).
 
Conclusions: Evidence on technical performance is mainly from the FDA-sponsored study. A strength of this study is the comparison of florbetapir imaging with the gold standard of post-mortem histopathology. Limitations include the small sample size, a majority rating for assessing diagnostic accuracy, and having only 2 patients in the mildly impaired category, which is the population for whom the test is most likely to be used. Evidence from this study indicates that the agreement between histopathology and beta-amyloid testing by PET is good but not perfect. 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.
 
Diagnostic Performance
The FDA-regulated study also included some information on diagnostic performance of the test. Using the majority consensus of three independent reviewers as the final test reading, sensitivity and specificity was calculated compared to the gold standard of histopathology (Clark 2011).  Of 15 subjects who met pathological criteria for AD, 14 had positive florbetapir scans (sensitivity of 93%). Of the 14 subjects who did not meet pathological criteria for AD, all 14 had negative scans (specificity of 100%). Scans from all of the young subjects (27 APOE4+ and 47 APOE-) were negative. Exploratory analysis indicated that in 3 subjects (20%), the clinical diagnosis did not match with the final autopsy diagnosis. These measures of diagnostic accuracy are limited by the patient population, which is not representative of the population that the test is intended to be used for, and the use of a majority reading based on three independent experts, which is not likely to be used in clinical care.
 
An industry-funded multicenter study by Fleisher et al. (2011) pooled data from 4 phase I and II trials of florbetapir-PET imaging for a total of 210 participants, including 68 subjects with probable AD, 60 subjects with mild cognitive impairment (MCI), and 82 older unimpaired controls.  Quantitative standard uptake value ratio (SUVRs) thresholds were determined from the phase III trial described above.  Although there were significant differences in mean SUVRs across groups, there was considerable overlap in the range of values. The percentage of subjects meeting threshold levels of amyloid with clinical AD, MCI and cognitively healthy controls was 80.9%, 40.0%, and 20.7%, respectively. The percentage of subjects with any identifiable florbetapir signal was 85.3%, 46.6%, and 28.1%, respectively. Among healthy controls, the percentage of subjects with any florbetapir positivity increased linearly by age, ranging from 11.8% for subjects 55 to 60 years of age to 41.7% for subjects 81 years of age or older. APOE4 carriers in the control group had about twice the percentage of florbetapir positivity as noncarriers, although this comparison did not reach statistical significance.
 
In 2012, Camus et al reported the diagnostic performance of florbetapir-PET in a clinical setting.  Included were 13 subjects with AD, 12 with MCI, and 21 older unimpaired controls. PET images were assessed visually by 2 readers who were blinded to any clinical information and quantitatively by the SUVR of cortical regions compared to the cerebellum. Sensitivity and specificity were calculated based on clinical diagnosis as the comparison standard. Agreement in visual analysis between the 2 readers gave 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 sensitivity of 84.6% and a specificity of 38.1% for discriminating AD patients from control subjects. A quantitative assessment of the global cortex SUVR showed a sensitivity of 92.3% and specificity of 90.5% at a cut-off value of 1.12 (ROC [receiver operating characteristics] area under the curve 0.894). Although the study is 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 assessment of the images.  In addition, quantitative analysis was not able to differentiate subjects with MCI from unimpaired controls.
 
Conclusions: Evidence on the diagnostic performance of beta-amyloid testing is limited, and the available studies all have methodologic limitations that limit the validity of reported results. As a result it is not possible to determine the sensitivity and specificity of testing. Some evidence suggests that there are a high number of false positive results in patients without AD. However, the FDA study reports high specificity, so the true rate of false positives is uncertain. Further high-quality studies using populations of patients that represent those presenting in clinical care are needed to better define the diagnostic performance of this test.
 
Clinical Outcomes
No trials have been identified that reported health outcomes following florbetapir-PET imaging, thus there is no direct evidence for clinical utility.
 
Possible clinical uses of beta-amyloid testing could include confirming the diagnosis of AD in order to begin medications at an earlier stage, or ruling out AD, which may lead to further diagnostic testing to determine the etiology of dementia and/or avoidance of anti-Alzheimer’s medications that would be unnecessary.
 
Since the sensitivity and specificity of beta-amyloid testing has not yet been established, it is not possible to determine an indirect chain of evidence that would indicate that health outcomes are improved. Because of the presence of beta amyloid in elderly patients who do not have AD, it is not likely that the test will have a high positive predictive value, and therefore it may have limited utility in confirming AD. It is possible that the negative predictive value of testing may be high, and that the test may be useful in ruling out AD.  If this is true, it is not certain how many patients would benefit from additional testing to determine etiology, or whether a substantial number of patients would avoid unnecessary medications that would otherwise be given.
 
In an editorial, Yang and colleagues discuss the clinical utility of florbetapir (Yang, 2012). The drug was developed to identify the presence of β-amyloid neuritic plaque in the brain which some clinicians view as a key to diagnosis of Alzheimer’s disease; but it is also detected in patients with normal cognition and other neurological disorders. According to the authors, “The prognostic usefulness of florbetapir imaging in identifying persons with mild cognitive impairment or cognitive symptoms who may be at risk for progression to dementia has not been determined. Nor are data available to determine whether florbetapir imaging could prove useful for predicting response to medications” (Yang, 2012).
  
Conclusions. Evidence on clinical utility, i.e. that health outcomes are improved by testing, is lacking. There are no studies that report on clinical outcomes following testing. The diagnostic accuracy of testing is too uncertain to determine whether testing is likely to impact management and/or lead to improved outcomes.
 
Ongoing Clinical Trials
A search of the online site www.clinicaltrials.gov in June 2012 identified a number of trials on amyloid imaging with PET. Of particular interest are the following:
• An industry-sponsored phase III open-label study to evaluate the efficacy and safety of florbetaben(BAY94-9172) PET imaging for detection/exclusion of cerebral beta-amyloid compared to postmortem histopathology (NCT01020838). This study has an estimated enrollment of 216 subjects with completion of the primary outcome measure in 2011 and final study completion in 2014.
• An industry-sponsored phase III open-label study to compare the brain uptake of flutemetamol with brain amyloid levels determined post-mortem (NCT01165554). The study has an estimated enrollment of 100 subjects with completion in 2012.
• An industry-sponsored phase III open-label study to assess the prognostic usefulness of flutemetamol for identifying subjects with amnestic MCI who will convert to clinically probable AD (NCT01028053). The study has an estimated enrollment of 225 subjects with completion estimated for January 2013.
 
Summary
Literature on the use of florbetapir-PET imaging to aid in the diagnosis of patients with suspected Alzheimer’s disease is limited. The pivotal phase III trial, although to be commended for its use of the gold standard of histopathology, has a number of limitations including small sample size, use of a majority rating of three physicians, and having few patients in the mildly impaired category. This study reported a moderately high correlation of amyloid plaque with histopathologic examination. The sensitivity and specificity of this test have not yet been adequately determined in an appropriate population, including a larger number of patients with mild cognitive impairment.
 
The clinical utility of this technology is uncertain. The test is not likely to be useful for confirming AD in patients who present with cognitive impairment. It may have a role in ruling out AD, but this has yet to be established with certainty. Questions also remain about the use of this test outside of the investigational setting, particularly regarding the accuracy of visual interpretation of images and how best to apply this test in routine clinical practice.
 
Practice Guidelines and Position Statements
2011 Guidelines from the National Institute on Aging and Alzheimer’s Association on the diagnosis of mild cognitive impairment and dementia due to Alzheimer’s disease recommend the use of biomarkers, including beta amyloid imaging with PET, only in research settings (McKhann 2011, Hyman 2012). Reasons for this recommendation are that more research needs to be done to ensure that the criteria that include the use of biomarkers have been appropriately designed, there is limited standardization of biomarkers from one locale to another; and access to biomarkers may be limited in community settings.
 
The Alzheimer’s Association, 2012, has indicated qualified support for the availability of florbetapir.  The statement includes the following: “On one hand, FDA approval of this product will expand the clinical and research opportunities for amyloid imaging by making this brain imaging tool more widely available to the field. On the other hand, the fact that all of the potential uses of this product are not crystal clear tempers our enthusiasm. Again, additional research is needed to clarify the role of florbetapir-PET imaging in Alzheimer’s.” The Alzheimer’s Association has convened a task force with the Society of Nuclear Medicine to develop recommendations for the use of amyloid imaging.
 
2013 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
 
Clark and colleagues published in August 2012 (Clark, 2012)  an extension of their previous U.S. Food and Drug Administration (FDA)-regulated study. This study reported on 59 participants with cognitive status ranging from normal to advanced dementia). Twelve participants had no cognitive impairment, 5 had MCI that did not meet the criteria for dementia, 29 had AD, and 13 had other forms of dementia. All patients had direct measurement of amyloid burden by histopathologic examination, and images were interpreted by three readers using a semiquantitative visual analysis 0-4. The median semiquantitative rating was used. A significant correlation of 0.76 and 0.79 was found between amyloid burden in the brain measured by Amyvid™ and the gold standard of histopathology in patients who had an autopsy performed within 2 years and 12 month of imaging, respectively. This report adds additional participants to those reported in the 2011 study described above (Clark, 2011).
 
The extension study used majority consensus of 5 independent reviewers rating the images on a binary scale of amyloid positive or negative as the final test reading. Sensitivity and specificity were calculated compared to the gold standard of histopathology. In 46 participants with a scan to autopsy time of less than 12 months, the sensitivity, specificity and accuracy were 96% (80-100), 100% (78-100) and 98% (87-100), respectively. For those with a scan to autopsy time of less than 2 years, the sensitivity, specificity and accuracy were 92% (78-98), 100% (78-100) and 95% (85-99), respectively.
 
Since the sensitivity and specificity of beta amyloid testing has not yet been established, it is not possible to determine an indirect chain of evidence that would indicate that health outcomes are improved. Because of the presence of beta amyloid in elderly patients who do not have AD, it is not likely that the test will have a high positive predictive value, and therefore it may have limited utility in confirming AD. It is possible that the negative predictive value of testing may be high and that the test may be useful in ruling out AD. If this is true, it is not certain how many patients would benefit from additional testing to determine etiology, or whether a substantial number of patients would avoid unnecessary medications that would otherwise be given.
 
In conclusion, evidence on clinical utility, i.e. that health outcomes are improved by testing, is lacking. There are no studies that report on clinical outcomes following testing. The diagnostic accuracy of testing is too uncertain to determine whether testing is likely to impact management and/or lead to improved outcomes.
 
Ongoing Clinical Trials
A search of the online site www.clinicaltrials.gov in May 2013 identified a number of trials on amyloid imaging with PET. Of particular interest are the following  is an industry sponsored Phase IV randomized trial to evaluate the effectiveness of Florbetapir PET imaging to change patient management and to evaluate the relationship between Florbetapir PET scan status and cognitive decline (NCT01703702). This study has an estimated enrollment of 600 subjects with completion of primary outcome measure and final study completion in December 2014.
 
Practice Guidelines and Position Statements
2013 Appropriate Use Criteria for Amyloid PET were developed jointly by The Society of Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association (Johnson, 2013).  They recommend that Amyloid imaging is appropriate for individuals with all of the following:
 
  1. A cognitive complaint with objectively confirmed impairment;
  2. A possible diagnosis of AD, but it remains uncertain after evaluation by a dementia expert;
  3. Knowledge that the presence or absence of Aβ pathology would increase the certainty of diagnosis and alter clinical management.
 
In the following situations:
 
  • Patients with persistent or progressive unexplained MCI
  • Patients satisfying core clinical criteria for possible AD because of unclear clinical presentation, either an atypical clinical course of an etiologically mixed presentation
  • Patients with progressive dementia and atypically early age of onset (usually defined as 65 years or less in age)
 
And inappropriate in the following situations:
 
  • Patients with core clinical criteria for probable AD with typical age of onset
  • To determine dementia severity
  • Based solely on a positive family history of dementia or presence of apolipoprotein E (APOE)ε4
  • Patients with a cognitive complaint that is unconfirmed on clinical examination
  • In lieu of genotyping for suspected autosomal mutation carriers
  • Nonmedical use (e.g., legal, insurance coverage, or employment setting)
 
2014 Update
A literature search conducted through August 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Mormino and colleagues did a study to determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals (Mormino, 2014). This study included an academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women). The measures and outcomes of the study used were the Aβ status was determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (Aβ-/ND-), stage 1 (Aβ+/ND-), stage 2 (Aβ+/ND+), and suspected non-Alzheimer disease pathology (Aβ-/ND+). Cognition was assessed with a composite of neuropsychological tests administered annually.
 
The co-occurrence of Aβ and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease is shown by, the Aβ+ CN individuals were more likely to be classified as ND+: 59.6% of Aβ+ CN individuals were ND+, whereas 31.9% of Aβ- CN individuals were ND+ (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both Aβ and ND, whereas diminished practice effects were observed in CN individuals positive for either Aβ or ND. Decline over time was observed only in CN individuals positive for both Aβ and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between Aβ and ND confirmed that this decline was greater than the additive contributions of Aβ and ND (P = .04).
 
Regional differences of the effect of WMH on cognition have been demonstrated but are not yet established as a biomarker in AD. In conclusion, biomarkers for amyloid and tau pathology allow a distinction between early and advanced stages of AD, but a subgroup of pathologically identified preclinical AD cases is not identified by the currently available biomarkers.
 
2015 Update
A literature search conducted through July 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Stefaniak and O’Brien performed a systematic search o the literature and found 28 studies that used in vivo neuroimaging of one or more markers of neuro-inflammation on human patients with dementia. The majority of the studies used positron emission tomography (PET) imaging of the TSPO microglial marker and found increased neuro-inflammation in at least one neuro-anatomical region in dementia patients, most usually Alzheimer's disease, relative to controls, but the published evidence to date does not indicate whether the regional distribution of neuro-inflammation differs between dementia types or even whether it is reproducible within a single dementia type between individuals. It is less clear that neuro-inflammation is increased relative to controls in mild cognitive impairment than it is for dementia, and therefore it is unclear whether neuro-inflammation is part of the pathogenesis in early stages of dementia. Despite its great potential, this review demonstrates that imaging of neuro-inflammation has not thus far clearly established brain inflammation as an early pathological event. Further studies are required, including those of different dementia subtypes at early stages, and newer, more sensitive, PET imaging probes need to be developed.
 
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2013, Vandenberghe and colleagues summarized published studies on test-retest variability and inter-rater reliability of all 3 tracers (Nayate, 2015). As shown in Table 1, variability in repeat testing was low for each agent, and inter-rater reliability varied from κ 0.6 to 0.96. Because values listed in Table 1 were derived from heterogeneous studies, cross-tracer comparisons are indirect.
 
Use of SUVR has been shown to decrease inter-reader variability of Florbetapir PET scan interpretation
(κ=0.92) compared to qualitatively read studies (κ=0.69) (Minoshima, 2015). However, as Minoshima noted in an accompanying editorial, if cases have differing impressions between qualitative interpretation and quantitative assessment, it is not known which is more accurate (Morris, 2016).  
 
2018 Update
A literature search conducted through December 2018 using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2018. No new literature was identified that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through February 2020.  There was no new information identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Martinez et al conducted 3 Cochrane systematic reviews of the diagnostic accuracy of PET scan using florbetapir, florbetaben, and flutemetamol to detect people with MCI who will clinically progress to AD or other forms of dementia at follow-up (Martinez, 2017; Martinez 2017; Martinez 2017). The reviewers concluded that due to limited data available, varying sensitivity and specificity, and risk of bias limiting confidence in the conclusions, routine use of the technology could not be recommended.
 
The pathophysiological changes and clinical manifestations of AD are progressive and occur along a continuum, and accumulation of amyloid beta may begin 20 years or more before symptoms arise (Vermunt 2019). National Institute on Aging-Alzheimer’s Association (NIA-AA) have created a “numeric clinical staging scheme” that avoids traditional syndromal labels and is applicable for only those in the Alzheimer continuum. This staging scheme reflects the sequential evolution of AD from an initial stage characterized by the appearance of abnormal AD biomarkers in asymptomatic individuals. As biomarker abnormalities progress, the earliest subtle symptoms become detectable. Further progression of biomarker abnormalities is accompanied by progressive worsening of cognitive symptoms, culminating in dementia. This numeric cognitive staging scheme is not designed to be used in a clinical setting but to be used for interventional trials such as those of aducanumab. The phase 3 RCTs for aducanumab were stratified to include 80% of stage 3 patients and 20% of stage 4 patients. This numeric staging scheme is very similar to the categorical system for staging AD outlined in the FDA guidance for industry pertaining to developing drugs for treatment of early AD (FDA, 2018).
 
As per the FDA 2018 draft guidance for developing drugs for treatment of early AD, treatment for mild to moderate AD dementia (corresponding to stages 4 and 5) would be considered substantially effective if there is improvement on a core symptom (eg, a measure of cognition) and a global clinical measure (eg, a clinician’s judgement of change) or a functional measure (eg, activities of daily living) (FDA,2018).
 
Evidence about the clinical utility of amyloid beta PET imaging to select patients for treatment with amyloid beta targeting-therapy is available from 4 studies conducted as part of the clinical development program for aducanumab. PRIME was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging, staggered study conducted in the United States with the primary objectives of safety and tolerability. The phase 3 studies were multicenter, global, randomized, double-blind, placebo-controlled studies of identical design with the primary objective of efficacy and safety. In all 3 studies, the diagnosis of AD was confirmed by presence of amyloid pathology measured by 18-florbetapir PET imaging. The pivotal trials ensured enrollment of patients at an earlier stage of their disease; MCI due to AD or mild AD dementia based on an entry criteria (FDA/PCNS, 2020).
 
The phase 3 studies randomized patients to aducanumab low dose (3 or 6 mg/kg for ApoE ε4 carriers and noncarriers, respectively), aducanumab high dose (10 mg/kg), or placebo every 4 weeks for 18 months, followed by an optional, dose-blind, long-term extension period. Due to early termination and consequent administrative censoring, data were missing for up to 45% of patients randomized in the 2 trials. Approximately, 60% of patients had the opportunity to complete week 78 of the trial before the trials were terminated for futility (FDA/PCNS, 2020).
 
Study 302 (N=1638 randomized patients) met the primary endpoint in patients treated with high-dose aducanumab (10 mg/kg) with an absolute difference of -0.39 in favor of aducanumab on the 18-point CDR-SB scale (a relative 22% less decline in high dose aducanumab group compared to placebo, p=.0120). The reported MCID is generally considered to be 1 to 2 points on a scale from 0 to 18 (Andrews, 2019). Results of responder analysis describing the proportion of individuals who achieved a predefined level of improvement was not reported. Results in the low-dose aducanumab (3 or 6 mg/kg for ApoE ε4 carriers and noncarriers, respectively), group were not statistically significant compared with placebo (absolute difference 0.26, relative difference 15%, p=.0901) and therefore no statistically valid conclusions can be made for any of the secondary endpoints for either treatment arm.
 
Study 301 (N=1647 randomized patients) did not meet its primary end point of a reduction relative to placebo in the CDR-SB score. For the high-dose arm, an absolute difference of 0.03 and a relative difference of 2% favored placebo (p=.8330). For the low-dose arm, an absolute difference of -0.18 and a relative difference of 12% favored aducanumab (p=.8330). Because of the pre-specified plans to control for type I error for multiple comparisons, no statistically valid conclusions can therefore be made for any of the secondary endpoints (FDA/PCNS, 2020).
 
Change in brain amyloid signal was measured by florbetapir fluorine 18 PET and quantified by a composite SUVR in a subset of sites and patients (n=488) at week 78. In study 302, adjusted mean change from baseline to week 78 relative to placebo showed a dose-dependent reduction in amyloid beta by -0.179 and -0.278 in the low- and high-dose arms, respectively. In study 301, adjusted mean change from baseline to week 78 relative to placebo showed a dose-dependent reduction in amyloid beta by -0.167 and -0.232 in the low- and high-dose arms, respectively. While aducanumab showed statistically significant dose dependent changes from baseline in amyloid beta plaques, there are no satisfactory data, clearly establishing individual changes in amyloid correlate with or predict long term cognitive and functional changes as measured by CDR-SB. The FDA statistical review reported no correlation in study 302 between reduction in amyloid plaque and long term clinical change among the high-dose cohort or full 10 mg/kg dosed subgroup. In the absence of clinical data convincingly demonstrating a clinical effect, it cannot be concluded that observed reduction in amyloid will translate into a clinical benefit to patients (FDA, 2020).
 
Data with limited follow-up are available to analyze safety because the phase 3 trials were stopped prematurely due to futility. Pooled safety data from the 2 phase 3 clinical trials showed that about 35% (compared to 3% in the placebo arm) of patients on aducanumab experienced amyloid-related imaging abnormalities (ARIA), whose clinical effects can range from asymptomatic to severe. Although the majority of patients were asymptomatic or had symptoms such as headache, confusion, or dizziness that resolved with temporary stoppage of the drug, 6.2% of participants receiving the high dose of aducanumab discontinued the drug due to ARIA (Aduhelm, 2021).
 
An increase in falling adverse events was observed in the high-dose as compared to placebo across the 2 phase 3 studies (15% vs. 12%, respectively). FDA statistical review ,reported a hazard ratio of 1.33 (p=.016) suggesting a 33% relative increase in hazard of falling for 10 mg/kg compared to placebo (FDA, 2020).
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Pichet et al (2022) published the results of a study that was aimed at identifying which combinations of AD related plasma biomarkers and other assessments provide the best prediction of progression to AD dementia in patients with mild cognitive impairment (MCI). The results of this study included data from a clinical trial (NCT010280530) which was a principal open-label study to assessing the prognostic usefulness of Flutemetamol (18F) injection in identifying patients with amnestic MCI who will convert to probable Alzheimer's Disease.
 
Zhu et al (2022) conducted a meta-analysis of cerebral perfusion imaging methods (FDG-PET, SPECT, and MRI) in the assessment of MCI conversion to AD. A total of 16 studies were included (5 with FDG-PET). The authors found significantly higher sensitivity, specificity, and positive likelihood ratio with FDG-PET than SPECT or MRI. The studies for FDG-PET were determined to have low risk of bias.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
78811Positron emission tomography (PET) imaging; limited area (eg, chest, head/neck)
78814Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; limited area (eg, chest, head/neck)
A4641Radiopharmaceutical, diagnostic, not otherwise classified
A9586Florbetapir f18, diagnostic, per study dose, up to 10 millicuries
A9601Flortaucipir f 18 injection, diagnostic, 1 millicurie
Q9982Flutemetamol f18, diagnostic, per study dose, up to 5 millicuries
Q9983Florbetaben f18, diagnostic, per study dose, up to 8.1 millicuries

References: 2021(2021) Alzheimer's disease facts and figures. Alzheimers Dement. Mar 2021; 17(3): 327-406. PMID 33756057

Albert MS, DeKosky ST, Dickson D et al.(2011) The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7:270-9.

Alzheimer's Association.(2012) Alzheimer's Association statement on FDA approval of florbetapir (Amyvid). http://www.alz.org/documents_custom/amyvid.pdf.

Alzheimer's Association.(2021) 2021 Alzheimers disease facts and figures. Published 2021. Available at https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf. Accessed September 9, 2021.

Andrews JS, Desai U, Kirson NY, et al.(2019) Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials. Alzheimers Dement (N Y). 2019; 5: 354-363. PMID 31417957

Ben Bouallegue F, Mariano-Goulart D, Payoux P, et al.(2018) Joint Assessment of Quantitative 18F-Florbetapir and 18F-FDG Regional Uptake Using Baseline Data from the ADNI. J Alzheimers Dis. 2018;62(1):399-408. PMID 29439345

Camus V, Payoux P, Barre L et al.(2012) Using PET with 18F-AV-45 (florbetapir) to quantify brain amyloid load in a clinical environment. Eur J Nucl Med Mol Imaging 2012; 39:621-31.

Ceccaldi M, Jonveaux T, Verger A, et al.(2018) Added value of (18)F-florbetaben amyloid PET in the diagnostic workup of most complex patients with dementia in France: A naturalistic study. Alzheimers Dement. Mar 2018;14(3):293-305. PMID 29107051

Clark CM, Pontecorvo MJ, Beach TG et al.(2012) Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet Neurol 2012; 11(8):669-78.

Clark CM, Schneider JA, Bedell BJ et al.(2011) Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011; 305:275-83.

Clark CM, Schneider JA, Bedell BJ, et al.(2011) Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA. Jan 19 2011;305(3):275-283. PMID 21245183

Eli Lilly and Company.(2013) Amyvid (florbetapir F18 injection) for intravenous use prescribing information, December 2013. http://pi.lilly.com/us/amyvid-uspi.pdf. Accessed September 23, 2021.

FDA Pre-Recorded Presentation Slides for the November 6, 2020:(2020) Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. Available at https://www.fda.gov/media/143504/download. Accessed on September 9, 2021

Fleisher AS, Chen K, Liu X et al.(2011) Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. Arch Neurol 2011; 68:1404-11.

GE Healthcare.(2016) Vizamyl (flutemetamol F18) injection prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203137s005lbl.pdf. Accessed September 23, 2021.

Hyman BT, Phelps CH, Beach TG et al.(2012) National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement 2012; 8:1-13.

Jansen WJ, Ossenkoppele R, Knol DL, et al.(2015) Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. May 19 2015; 313(19): 1924-38. PMID 25988462

Johnson KA, Minoshima S, Bohnen NI, et al.(2013) Appropriate use criteria for amyloid PET: A report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimer’s & Dementia. 2013. 1-15.

Lu ZK, Xiong X, Wang X, et al.(2021) Gender Disparities in Anti-dementia Medication Use among Older Adults: Health Equity Considerationsand Management of Alzheimer's Disease and Related Dementias. Front Pharmacol. 2021; 12: 706762. PMID 34512340

Martinez G, Vernooij RW, Fuentes Padilla P, et al.(2017) 18F PET with florbetaben for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. Nov 22 2017; 11: CD012883. PMID 29164600

Martinez G, Vernooij RW, Fuentes Padilla P, et al.(2017) 18F PET with florbetapir for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. Nov 22 2017; 11: CD012216. PMID 29164603

Martinez G, Vernooij RW, Fuentes Padilla P, et al.(2017) 18F PET with flutemetamol for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. Nov 22 2017; 11: CD012884. PMID 29164602

McKhann G, Drachman D, Folstein M, et al.(1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. Jul 1984;34(7):939-944. PMID 6610841

McKhann GM, Knopman DS, Chertkow H et al.(2011) The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7:263-9.

Minoshima S.(2015) Establishing amyloid PET imaging biomarkers: ongoing efforts {editorial]. AJNR Am J Neuroradiol. Jul 2015;36(7):1245-1246. PMID 25999415

Mitchell AJ, Shiri-Feshki M.(2009) Rate of progression of mild cognitive impairment to dementia--meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand. Apr 2009;119(4):252-265. PMID 19236314

Mormino EC, Betensky RA, Hedden T.(2014) Synergistic Effect of ß-Amyloid and Neurodegeneration on Cognitive Decline in Clinically Normal Individuals. JAMA Neurol. 2014 Sep 15. doi: 10.1001/jamaneurol.2014.2031

Morris E, Chalkidou A, Hammers A, et al.(2016) Diagnostic accuracy of (18)F amyloid PET tracers for the diagnosis of Alzheimer's disease: a systematic review and meta-analuysis. Eur J Nuci Med Mol Imaging. Feb 2016;43(2):374-385

National Institute on Aging.(2021) Data shows racial disparities in Alzheimers disease diagnosis between Black and white research studyparticipants. 2021. https://www.nia.nih.gov/news/data-shows-racial-disparities-alzheimers-disease-diagnosis-between-black-and-white-research.

Nayate AP, Dubroff JG, Schmitt JE, et al.(2015) Use of standardized uptake value ratios decreases interreader variability of [18F] Florbetapir PET brain scan interpretation. AJNR Am J Neuroradiol. Mar 12 2015. PMID 25767185

NIH(2022) 2022 Alzheimer's disease facts and figures. Alzheimers Dement. Apr 2022; 18(4): 700-789. PMID 35289055

Ossenkoppele R, Jansen WJ, Rabinovici GD, et al.(2015) Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA. May 19 2015; 313(19): 1939-49. PMID 25988463

PCNS Drugs Advisory Committee.(2020) Combined FDA and Applicant PCNS Drugs Advisory Committee Briefing Document: Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee Meeting- November 6, 2020. Available at https://www.fda.gov/media/143502/download Accessed September 9, 2021

Pichet Binette A, Palmqvist S, Bali D, et al.(2022) Combining plasma phospho-tau and accessible measures to evaluate progression toAlzheimer's dementia in mild cognitive impairment patients Alzheimers Res Ther. Mar 29 2022; 14(1): 46. PMID 35351181

Piramal Imaging.(2014) Neuraceq (florbetaben F 18 injection) for intravenous use prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204677s000lbl.pdf. Accessed September 23,2021.

Pontecorvo MJ, Siderowf A, Dubois B, et al.(2017) Effectiveness of Florbetapir PET Imaging in Changing Patient Management. Dement Geriatr Cogn Disord. 2017;44(3-4):129-143. PMID 28787712

Roberts RO, Aakre JA, Kremers WK, et al.(2018) Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting. JAMA Neurol. Aug 01 2018; 75(8): 970-979. PMID 29710225

Stefaniak J, O'Brien J.(2015) Imaging of neuroinflammation in dementia: a review. J Neurol Neurosurg Psychiatry. 2015 Sep 18. pii: jnnp-2015-311336.

U.S. Food and Drug Administration.(2011) FDA Advisory Committee briefing document: Peripheral and central nervous system drugs advisory committee. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM240265.pdf?utm_campaign=Google2&utm_source=fdaSearch&utm_medium=website&utm_term=amyvid&utm_content=5.

US Food and Drug Administration (FDA).(2018) Early Alzheimers disease: developing drugs for treatment guidance for industry. Draft Guidance. Published online Feb 29, 2018. Available at https://www.fda.gov/media/110903/download. Accessed on September 9, 2021

Vallabhajosula S (1).(2011) Positron emission tomography radiopharmaceuticals for imaging brain Beta-amyloid. Semin Nucl Med 2011; 41:283-99.

Vallabhajosula S (2), Solnes L, Vallabhajosula B.(2011) A broad overview of positron emission tomography radiopharmaceuticals and clinical applications: what is new? Semin Nucl Med 2011; 41:246-64.

Vermunt L, Sikkes SAM, van den Hout A, et al.(2019) Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype. Alzheimers Dement. Jul 2019; 15(7): 888-898. PMID 31164314

Wolk DA, Sadowsky C, Safirstein B, et al.(2018) Use of flutemetamol F 18-Labeled positron emission tomography and other biomarkers to assess risk of clinical progression in patients with amnestic mild cognitive impairment. JAMA Neurol. May 14 2018. PMID 29799984

Yang L., Rieves D., Ganley C.(2012) Brain amyloid amaging-FDA approval of florbetapir F18 injection. NEJM 367;10:885-887.

Zhu L, Zhao W, Chen J, et al.(2022) Systematic review and meta-analysis of diagnostic test accuracy (DTA) studies: the role of cerebralperfusion imaging in prognosis evaluation of mild cognitive impairment. Ann Palliat Med. Feb 2022; 11(2): 673-683. PMID 35249345


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