Selected Positron Emission Tomography Technologies for Evaluation of Alzheimer Disease

POLICY NUMBER

A.6.01.55

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. 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.

One radioactive tracer (flortaucipir F18) that binds to aggregated tau protein and can be detected in vivo with PET has been approved by the FDA for tau imaging in patients with cognitive impairment who are being evaluated for AD 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, tau pathology, 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, 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.

The other defining pathologic hallmark of AD is tau neurofibrillary tangles (NFTs). Postmortem studies have found that NFTs more directly correlate to the severity of dementia and neurodegeneration compared to amyloid beta plaques.

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 January 2023, lecanemab (Leqembi®; Eisai) was approved by the FDA for the treatment of AD under accelerated approval, which was converted to traditional approval in July 2023. In July 2024, donanemab (Kisunla, Eli Lilly) was approved by the FDA via a traditional approval for the treatment of AD in patients with mild cognitive impairment or mild dementia stage of disease. The labeled indication for both lecanemab and donanemab is for the treatment of AD in patients with mild cognitive impairment or mild dementia stage of disease. The labels indicates that the presence of amyloid beta pathology should be confirmed prior to initiating treatment.

Radiopharmaceuticals for Positron Emission Tomography Imaging

The following PET radiopharmaceuticals have been evaluated and approved as drugs by the FDA for use as diagnostic imaging agents in individuals with cognitive impairment.

Radioactive Tracers Approved by the FDA for PET Imaging in Individuals with Cognitive Impairment

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.

• Dopamine Transporter Imaging with Single-Photon Emission Computed Tomography

• Evaluation of Biomarkers for Alzheimer Disease

• Miscellaneous (Noncardiac, Nononcologic) Applications of Fluorine 18 Fluorodeoxyglucose Positron Emission Tomography

POLICY

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 medically necessary (see Policy Guidelines).

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 evaluate individuals with mild cognitive impairment or mild dementia due to Alzheimer disease for continuation of amyloid beta plaque-targeting therapy is considered investigational.

Tau imaging with PET to predict conversion to Alzheimer disease is considered investigational.

Tau imaging with PET as an adjunct to clinical diagnosis in individuals with dementia is considered investigational.

Tau 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.

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.

POLICY EXCEPTIONS

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.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

The labels for FDA-approved, amyloid beta targeting therapies (see Monoclonal Antibodies for Treatment of Alzheimer’s Disease / State and School Employees' Health Insurance Plan - Monoclonal Antibodies for Treatment of Alzheimer’s Disease) state that the presence of amyloid beta pathology should be confirmed prior to initiating treatment. In the pivotal randomized controlled trial for lecanemab (Clarity AD), the protocol states that the eligibility criteria related to amyloid beta pathology required 'confirmed amyloid pathology indicated by either 1) positive amyloid load confirmed by amyloid PET assessment, or 2) CSF assessment of t-tau / Aβ[1-42].' The protocol for the pivotal randomized trial for donanemab (TRAILBLAZER-ALZ 2) states that the eligibility criteria related to amyloid beta pathology required that the patient must 'meet flortaucipir F18 scan (central read) criteria'.

Lecanemab Monitoring

The product label of lecanemab recommends that a baseline brain MRI within 1 year must be done prior to initiating treatment due to the risk of amyloid-related imaging abnormalities (ARIA). Subsequently, MRI should be repeated prior to the fifth, seventh, and fourteenth infusions. Follow recommendations for dosing interruptions in individuals with ARIA as specified in the US FDA-approved prescribing label.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B. appropriate with regard to standards of good medical practice; and

C. not solely for the convenience of the Member, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good 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. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

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.

POLICY HISTORY

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."

07/01/2026: Policy description updated regarding tau protein, neurofibrillary tangles, treatments, and radiopharmaceuticals for PET imaging. Policy statement changed from investigational to medically necessary for 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. Added investigational statements for tau imaging with PET. Policy Guidelines updated regarding amyloid beta targeting therapies and to define medically necessary. Code Reference section updated to change the following codes from investigational to medically necessary: CPT codes 78811, 78814, A9586, Q9982, and Q9983. Added ICD-10 diagnosis codes G30.0 - G30.9. Removed HCPCS codes A4641 and A9598 from the policy.

SOURCE(S)

Blue Cross Blue Shield Association policy # 6.01.55 

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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