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A.6.01.55
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. 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).
Three radioactive tracers (florbetapir fluorine 18, florbetaben fluorine 18, flutemetamol fluorine 18) that bind to amyloid beta and can be detected in vivo with PET have been approved by the U.S. Food and Drug Administration (FDA) for amyloid beta imaging in patients who are being evaluated for cognitive decline. Amyloid beta plaque PET imaging is proposed as an adjunct to the clinical diagnosis of AD and as a component of identifying patients for amyloid beta plaque-targeting therapy.
Fluorine 18 fluorodeoxyglucose PET (FDG-PET) quantifies brain function by measuring glucose levels. FDG-PET is proposed as a method to distinguish AD from other dementias through identifying distinct regions of hypometabolism.
Alzheimer Disease
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 6.5 million Americans aged 65 and older are currently living with AD dementia, and the number is projected to reach over 13.8 million by 2060.
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.
There is evidence of healthcare disparity in AD. Studies have shown that Black Americans are 1.5 to 2 times more likely than White Americans to develop AD; however, in research studies, Black participants were 35% less likely to be diagnosed with AD or similar dementias. Similarly, recent evidence indicates gender disparities as well, with females with AD 1.7 times more likely to receive treatment for dementia compared with males.
Role of Positron Emission Tomography
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 amyloid beta plaques 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, they may be absent in a substantial proportion of patients with clinical features of AD.
18-F fluorodeoxyglucose PET (18-F FDG PET) quantifies brain function by measuring glucose levels. Through identifying distinct regions of hypometabolism, FDG-PET is proposed as a method to distinguish AD from other dementias, especially in patients with atypical presentations (e.g., younger age).
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.
Treatment Options
Current treatment goals for patients with AD are often directed to maintain quality of life, treat cognitive symptoms, and manage behavioral and psychological symptoms of dementia. Treatment remains largely supportive, including creation and implementation of individualized dementia care plans, caregiver education and support, care navigation, care coordination, and referral to community-based organizations for services (eg, adult day care, caregiver training, etc). Non-pharmacologic treatments include physical activity, as well as behavioral strategies to ameliorate neuropsychiatric symptoms (eg, agitation, delusions, disinhibition), and problem behaviors (eg, resistance to care, hoarding, obsessive-compulsive behaviors).
U.S. Food and Drug Administration (FDA)-approved drugs for AD symptoms include the cholinesterase inhibitors donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate antagonist, memantine. These drugs, either alone or in combination, focus on managing cognitive and functional symptoms of the disease and have not been shown to alter disease trajectory. The evidence for efficacy is limited and these agents are associated with significant side effects.
In June 2021, aducanumab (Aduhelm®; Biogen) was approved by the FDA for treatment of AD. This indication was approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with aducanumab. Continued approval for this indication is contingent upon verification of clinical benefit in confirmatory trial(s). The FDA, under the accelerated approval regulations (21 CFR 601.41), requires that Biogen conduct a randomized, controlled trial to evaluate the efficacy of aducanumab compared to an appropriate control for the treatment of AD. The trial should be of sufficient duration to observe changes on an acceptable endpoint in the patient population enrolled in the trial. The expected date of trial completion is August 2029 and final report submission to the FDA by February 2030.
In July 2021, the FDA amended the approved label to emphasize the disease stages studied in the clinical trials. The amended label states, "Treatment with aducanumab should be initiated in patients with MCI or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied."
Radiopharmaceuticals for PET Imaging
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™ (see the table below) 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 Alzheimer disease and other causes of cognitive decline.”
In 1994, the fludeoxyglucose (FDG) F18 radiotracer was originally approved by the FDA through the New Drug Application (NDA) process (NDA20306). The original indication was for "the identification of regions of abnormal glucose metabolism associated with foci of epileptic seizures." Added indications in 2000 were for "Assessment of glucose metabolism to assist in the evaluation of malignancy…" and "Assessment of patients with coronary artery disease and left ventricular dysfunction…." FDA approval of FDG does not include the evaluation of patients with cognitive decline. Multiple manufacturers have approved NDAs for FDG.
The prescribing information for all 3 agents used for amyloid beta imaging states:
The objective of amyloid beta amyloid image interpretation “is to estimate beta-amyloid neuritic plaque density in brain gray matter, not to make a clinical diagnosis.”
A positive amyloid beta scan “does not establish the diagnosis of AD or other cognitive disorder.”
A negative amyloid beta 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 Patients with Cognitive Impairment
Agent | Trade Name | Manufacturer | NDA | Approved |
florbetapir F18 | Amyvid | Avid Radiopharmaceuticals (subsidiary of Eli Lilly) | 202008 | 2012 |
flutemetamol F18 | Vizamyl | GE Healthcare | 203137 | 2013 |
florbetaben F18 | Neuraceq | Piramal Life Sciences | 204677 | 2014 |
NDA: new drug application.
This policy does not currently include tau PET imaging.
Related medical policies are –
Amyloid beta imaging with positron emission tomography (PET) to predict conversion to Alzheimer disease is considered investigational.
Amyloid beta imaging with PET as an adjunct to clinical diagnosis in individuals with dementia is considered investigational.
Amyloid beta imaging with PET to select individuals with mild cognitive impairment or mild dementia due to Alzheimer disease for amyloid beta targeting plaque-therapy is considered investigational.
Amyloid beta imaging with PET to evaluate individuals with mild cognitive impairment or mild dementia due to Alzheimer disease for continuation of amyloid beta plaque-targeting therapy is considered investigational.
PET Imaging with fluorine 18 fluorodeoxyglucose (FDG-PET) as an adjunct to clinical diagnosis in individuals with dementia is considered investigational.
All other uses of amyloid beta imaging with positron emission tomography (PET) are considered investigational.
Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
11/15/2012: Approved by Medical Policy Advisory Committee.
10/23/2013: Policy reviewed; no changes.
02/26/2014: Added the following new 2014 HCPCS code(s) to the Code Reference section: A9599.
08/06/2014: Policy reviewed; description updated regarding radioactive diagnostic imaging agents and prescribing information. Policy statement revised to remove "considered." It previously stated: Beta amyloid imaging with positron emission tomography (PET) is considered investigational.
07/08/2015: Code Reference section updated for ICD-10.
10/30/2015: Policy description updated regarding the presence of beta amyloid in individuals. Policy statement unchanged. Investigative definition updated in policy guidelines section.
05/31/2016: Policy number A.6.01.55 added.
10/13/2016: Policy reviewed; no changes.
12/30/2016: Code Reference section updated to add new 2017 HCPCS code A9598. Revised code description for HCPCS code A9599.
10/18/2017: Policy description updated regarding diagnosis of Alzheimer disease. Policy statement unchanged.
12/22/2017: Code Reference section updated to make note of deleted HCPCS code A9599 effective 12/31/2017.
10/08/2018: Policy description updated regarding diagnosis of Alzheimer Disease and FDA-Approved agents. Policy statement unchanged.
10/31/2019: Policy reviewed; no changes. Code Reference section updated to remove deleted HCPCS code A9599.
10/15/2020: Policy reviewed; no changes.
10/24/2022: Policy title changed from "Beta Amyloid Imaging with Positron Emission Tomography for Alzheimer Disease" to "Selected Positron Emission Tomography Technologies for Evaluation of Alzheimer Disease." Policy description extensively revised regarding Alzheimer disease, positron emission tomography, treatment options, and radiopharmaceuticals for PET imaging. Added investigational statements regarding amyloid beta imaging with PET. Added investigational statement regarding PET imaging with fluorine 18 fluorodeoxyglucose. Code Reference section updated to add HCPCS codes A9586, Q9982, and Q9983.
12/14/2022: Policy description updated regarding healthcare disparities in Alzheimer disease. Policy statements updated to change "patients" to "individuals."
Blue Cross Blue Shield Association policy # 6.01.55
Code Number | Description |
CPT-4 | |
78811 | Positron emission tomography (PET) imaging; limited area (eg, chest, head/neck) |
78814 | Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; limited area (eg, chest, head/neck) |
HCPCS | |
A4641 | Radiopharmaceutical, diagnostic, not otherwise classified |
A9586 | Florbetapir F18, diagnostic, per study dose, up to 10 millicuries |
A9598 | Positron emission tomography radiopharmaceutical, diagnostic, for non-tumor identification, not otherwise classified |
Q9982 | Flutemetamol F18, diagnostic, per study dose, up to 5 millicuries |
Q9983 | Florbetaben F18, diagnostic, per study dose, up to 8.1 millicuries |
ICD-10 Procedure | |
ICD-10 Diagnosis |
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