Which Clinical Scenarios Warrant Amyloid PET?

LOS ANGELES—Amyloid PET scans may play an important role in neurologists’ management of patients with cognitive impairment. For the moment, clinical use should be restricted to cases that can be summarized with the mnemonic MAY—Mild, Atypical, and Young, said Gil D. Rabinovici, MD. “Those are the people who are most likely to benefit,” he said.

Although amyloid PET scans may affect diagnostic certainty and influence treatment in these scenarios, most patients do not get the scans. “They cost thousands of dollars, and most insurance will not pay for them,” Dr. Rabinovici said in a lecture at the 70th Annual Meeting of the American Academy of Neurology.

Looking to the future, amyloid PET may play a larger role in clinical practice if insurance providers more readily cover the cost of the scans and if the definition of Alzheimer’s disease shifts from a clinical basis to a biologic one. Someday, neurologists may be able to offer interventions to delay or prevent the onset of dementia in patients at risk of Alzheimer’s disease, Dr. Rabinovici said.“During the coming decade, we are going to see a real paradigm shift,” he said, “from the current status quo where we are diagnosing and treating clinical dementia to a paradigm where we are doing early screening with biomarkers.” Dr. Rabinovici is the Edward Fein and Pearl Landrith Distinguished Professor in the Memory and Aging Center at the University of California, San Francisco.

Three FDA-Approved Tracers

Three amyloid-beta tracers are FDA approved for clinical use in cognitively impaired patients—18F-florbetapir (Amyvid, approved in 2012), 18F-flutemetamol (Vizamyl, approved in 2013), and 18F-florbetaben (Neuraceq, approved in 2014).

The agents were approved on the basis of studies that found that blinded visual reads of amyloid PET scans during life accurately predicted postmortem burden of amyloid pathology in the same individuals. The scans distinguish patients with moderate or frequent neuritic plaques from those with absent or sparse neuritic plaques with a sensitivity and specificity of 80% or greater. Many scans can be categorized as positive or negative, and neurologists can quickly learn to read them, Dr. Rabinovici said.

Scans have the potential to improve the accuracy of Alzheimer’s disease diagnosis. Compared with postmortem findings, the clinical diagnosis of probable Alzheimer’s disease was accurate only 70% of the time in one study. Conversely, another study found that approximately 40% of patients with a diagnosis of non-Alzheimer’s disease dementia turned out to have Alzheimer’s disease as the primary causative pathology at autopsy.

Real-Life Ramifications

To illustrate amyloid PET’s potential usefulness in clinical practice, Dr. Rabinovici described a case of a 57-year-old internist. The patient had progressive trouble finding words, but otherwise did not have major symptoms or concerns. He did poorly on repeating sentences, but the rest of his examination was normal. MRI revealed nothing remarkable.

“That is the typical standard of care that is meant for someone with a cognitive complaint,” Dr. Rabinovici said. An FDG-PET scan was suspicious but not definitive. The patient’s amyloid PET scan, however, was clearly positive and showed amyloid throughout the neocortex. “With the scans, I could diagnose him. He had mild cognitive impairment, but I thought with high likelihood due to Alzheimer’s disease.”

As a result, Dr. Rabinovici started the patient on a cholinesterase inhibitor, and the patient decided to retire early due to medical disability. In addition, the patient enrolled in a clinical trial of an investigational antiamyloid therapy.

“I was not able to cure or modify the course of his Alzheimer’s disease, but amyloid PET did have real ramifications for his life,” he said.

 

Consider the Clinical Context

As with any diagnostic agent, clinical context is critical for interpreting the significance of positive and negative amyloid scans, Dr. Rabinovici said.

Among patients with dementia, amyloid PET can distinguish Alzheimer’s disease from conditions that do not involve amyloid-beta deposition, such as frontotemporal dementia or pure vascular dementia. It is not useful, however, in distinguishing Alzheimer’s disease from other conditions in which amyloid is deposited in the brain, such as cerebral amyloid angiopathy or dementia with Lewy bodies.

“It is important to consider the patient’s age when you think about the meaning of a positive scan,” he said. “A negative scan is always helpful in ruling out Alzheimer’s disease,” but a positive scan is less meaningful in older patients. Approximately 25% of cognitively normal older individuals have positive amyloid PET scans. The prevalence of amyloid positivity is about 10% at age 60 and more than 50% at age 90.

Not everyone with amyloid deposition has or develops Alzheimer’s disease dementia or mild cognitive impairment, but amyloid is a risk factor, said Dr. Rabinovici. “To summarize 15 years of research in one bullet point, it is not good to have amyloid in your brain even if you are cognitively normal,” he said. “Amyloid-positive normal controls are already showing Alzheimer’s-disease-like structural and functional changes in their brains. Over time, they are likely to decline cognitively. And they have an increased risk of cognitive impairment,” compared with people who are amyloid negative.

Research indicates that the deposition of amyloid plaques begins at least 15 years before the onset of cognitive symptoms, which may represent a window for early intervention, Dr. Rabinovici said.

When to Scan and When Not To

To guide clinicians in the appropriate use of amyloid PET, the Society for Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association in 2013 published appropriate use criteria for the technology. Given amyloid PET’s cost and need for nuanced interpretation, the authors determined that it should not be a first-line test in the evaluation of cognitive complaints, Dr. Rabinovici said. Rather, it should be an ancillary test ordered by subspecialists in patients who meet the following criteria:

• Have a cognitive complaint with objectively confirmed impairment.
• Have an uncertain diagnosis, with Alzheimer’s disease as a possibility, after comprehensive evaluation by a dementia expert.
• Knowledge of their amyloid-beta status is expected to increase diagnostic certainty and alter management.

The three main clinical scenarios in which amyloid imaging may be most useful include the following:

• Cases with persistent and progressive unexplained mild cognitive impairment.
• Cases with possible (rather than probable) Alzheimer’s disease who have an atypical or mixed course or significant comorbidities (eg, vascular, psychiatric, or substance abuse disorders).
• Cases with an atypically early age of onset (ie, younger than 65).

The appropriate use criteria also highlight the following scenarios in which clinical amyloid PET is considered inappropriate:

 

• For the initial evaluation of cognitive complaints.
• To screen cognitively normal individuals outside the context of research or clinical trials.
• When requested solely based on a family history of dementia or the presence of other Alzheimer’s disease risk factors, such as the ApoE4 gene.
• As a substitute for genetic testing for mutations that cause Alzheimer’s disease.
• For nonmedical reasons, such as insurance, legal, or employment decisions.

Finally, the criteria identify scenarios where amyloid imaging is unlikely to be useful, including as a means of determining the severity of dementia, straightforward clinical cases, and to differentiate Alzheimer’s disease from other diseases that involve the deposition of amyloid-beta.

Effects on Management and Outcomes

Relatively few studies have assessed amyloid PET’s impact on clinical decision making and patient outcomes, Dr. Rabinovici said. In 2013, the US Centers for Medicare and Medicaid Services (CMS) determined that there was insufficient evidence to justify reimbursement of amyloid PET and said that it would reimburse the scans for patients who enroll in studies to assess amyloid PET’s clinical utility, under a mechanism called coverage with evidence development. For CMS to reconsider its coverage decision, studies must demonstrate that amyloid PET changes patient management in the short term and improves dementia outcomes long term. The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which Dr. Rabinovici chairs, is a multisite study to assess the utility of amyloid PET in Medicare beneficiaries age 65 and older who meet appropriate use criteria for amyloid imaging.

The IDEAS study enrolled more than 18,000 participants and finished recruiting patients this year. It aims to examine how the scans affect patient management plans at three months and medical outcomes at 12 months. “The primary hypothesis is that, in these diagnostically uncertain cases, knowing the amyloid result will change management, and that will translate into better outcomes,” Dr. Rabinovici said.

Results regarding amyloid PET’s influence on patient management at three months will be presented soon, and 12-month outcome data are expected to be presented in 2019.

An interim analysis of the first 3,979 patients found that, three months after the amyloid PET scans, patients’ management plans had changed from the pre-PET management plan in about 67% of cases. Changes included starting or stopping Alzheimer’s-disease-specific medications and other neurologic therapies and changes in patient counseling.

Matched With Controls

To assess 12-month outcomes, investigators plan to use Medicare claims data to compare medical outcomes for patients enrolled in the study with those for matched controls who did not undergo amyloid PET. The primary objective is to determine whether amyloid PET is associated with a 10% or greater reduction in hospitalizations and emergency room visits. The researchers plan to use an algorithm to match each IDEAS study participant with a control with a similar dementia diagnosis, pre-scan dementia-related resource utilization, age, race, gender, ethnicity, geographic location, and comorbid chronic conditions.

Further imaging advances, such as tau PET tracers, are in development but have not yet received regulatory approval from the FDA, Dr. Rabinovici said. Tau PET has the potential to detect pathology in tauopathies such as progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and subtypes of frontotemporal dementia, as well as Alzheimer’s disease, he said.

—Jake Remaly

Suggested Reading

Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.

Johnson KA, Minoshima S, Bohnen NI, et al. 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. Alzheimers Dement. 2013;9(1):e1-e16.

LOS ANGELES—Amyloid PET scans may play an important role in neurologists’ management of patients with cognitive impairment. For the moment, clinical use should be restricted to cases that can be summarized with the mnemonic MAY—Mild, Atypical, and Young, said Gil D. Rabinovici, MD. “Those are the people who are most likely to benefit,” he said.

Although amyloid PET scans may affect diagnostic certainty and influence treatment in these scenarios, most patients do not get the scans. “They cost thousands of dollars, and most insurance will not pay for them,” Dr. Rabinovici said in a lecture at the 70th Annual Meeting of the American Academy of Neurology.

Looking to the future, amyloid PET may play a larger role in clinical practice if insurance providers more readily cover the cost of the scans and if the definition of Alzheimer’s disease shifts from a clinical basis to a biologic one. Someday, neurologists may be able to offer interventions to delay or prevent the onset of dementia in patients at risk of Alzheimer’s disease, Dr. Rabinovici said.“During the coming decade, we are going to see a real paradigm shift,” he said, “from the current status quo where we are diagnosing and treating clinical dementia to a paradigm where we are doing early screening with biomarkers.” Dr. Rabinovici is the Edward Fein and Pearl Landrith Distinguished Professor in the Memory and Aging Center at the University of California, San Francisco.

Three FDA-Approved Tracers

Three amyloid-beta tracers are FDA approved for clinical use in cognitively impaired patients—18F-florbetapir (Amyvid, approved in 2012), 18F-flutemetamol (Vizamyl, approved in 2013), and 18F-florbetaben (Neuraceq, approved in 2014).

The agents were approved on the basis of studies that found that blinded visual reads of amyloid PET scans during life accurately predicted postmortem burden of amyloid pathology in the same individuals. The scans distinguish patients with moderate or frequent neuritic plaques from those with absent or sparse neuritic plaques with a sensitivity and specificity of 80% or greater. Many scans can be categorized as positive or negative, and neurologists can quickly learn to read them, Dr. Rabinovici said.

Scans have the potential to improve the accuracy of Alzheimer’s disease diagnosis. Compared with postmortem findings, the clinical diagnosis of probable Alzheimer’s disease was accurate only 70% of the time in one study. Conversely, another study found that approximately 40% of patients with a diagnosis of non-Alzheimer’s disease dementia turned out to have Alzheimer’s disease as the primary causative pathology at autopsy.

Real-Life Ramifications

To illustrate amyloid PET’s potential usefulness in clinical practice, Dr. Rabinovici described a case of a 57-year-old internist. The patient had progressive trouble finding words, but otherwise did not have major symptoms or concerns. He did poorly on repeating sentences, but the rest of his examination was normal. MRI revealed nothing remarkable.

“That is the typical standard of care that is meant for someone with a cognitive complaint,” Dr. Rabinovici said. An FDG-PET scan was suspicious but not definitive. The patient’s amyloid PET scan, however, was clearly positive and showed amyloid throughout the neocortex. “With the scans, I could diagnose him. He had mild cognitive impairment, but I thought with high likelihood due to Alzheimer’s disease.”

As a result, Dr. Rabinovici started the patient on a cholinesterase inhibitor, and the patient decided to retire early due to medical disability. In addition, the patient enrolled in a clinical trial of an investigational antiamyloid therapy.

“I was not able to cure or modify the course of his Alzheimer’s disease, but amyloid PET did have real ramifications for his life,” he said.

 

Consider the Clinical Context

As with any diagnostic agent, clinical context is critical for interpreting the significance of positive and negative amyloid scans, Dr. Rabinovici said.

Among patients with dementia, amyloid PET can distinguish Alzheimer’s disease from conditions that do not involve amyloid-beta deposition, such as frontotemporal dementia or pure vascular dementia. It is not useful, however, in distinguishing Alzheimer’s disease from other conditions in which amyloid is deposited in the brain, such as cerebral amyloid angiopathy or dementia with Lewy bodies.

“It is important to consider the patient’s age when you think about the meaning of a positive scan,” he said. “A negative scan is always helpful in ruling out Alzheimer’s disease,” but a positive scan is less meaningful in older patients. Approximately 25% of cognitively normal older individuals have positive amyloid PET scans. The prevalence of amyloid positivity is about 10% at age 60 and more than 50% at age 90.

Not everyone with amyloid deposition has or develops Alzheimer’s disease dementia or mild cognitive impairment, but amyloid is a risk factor, said Dr. Rabinovici. “To summarize 15 years of research in one bullet point, it is not good to have amyloid in your brain even if you are cognitively normal,” he said. “Amyloid-positive normal controls are already showing Alzheimer’s-disease-like structural and functional changes in their brains. Over time, they are likely to decline cognitively. And they have an increased risk of cognitive impairment,” compared with people who are amyloid negative.

Research indicates that the deposition of amyloid plaques begins at least 15 years before the onset of cognitive symptoms, which may represent a window for early intervention, Dr. Rabinovici said.

When to Scan and When Not To

To guide clinicians in the appropriate use of amyloid PET, the Society for Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association in 2013 published appropriate use criteria for the technology. Given amyloid PET’s cost and need for nuanced interpretation, the authors determined that it should not be a first-line test in the evaluation of cognitive complaints, Dr. Rabinovici said. Rather, it should be an ancillary test ordered by subspecialists in patients who meet the following criteria:

• Have a cognitive complaint with objectively confirmed impairment.
• Have an uncertain diagnosis, with Alzheimer’s disease as a possibility, after comprehensive evaluation by a dementia expert.
• Knowledge of their amyloid-beta status is expected to increase diagnostic certainty and alter management.

The three main clinical scenarios in which amyloid imaging may be most useful include the following:

• Cases with persistent and progressive unexplained mild cognitive impairment.
• Cases with possible (rather than probable) Alzheimer’s disease who have an atypical or mixed course or significant comorbidities (eg, vascular, psychiatric, or substance abuse disorders).
• Cases with an atypically early age of onset (ie, younger than 65).

The appropriate use criteria also highlight the following scenarios in which clinical amyloid PET is considered inappropriate:

 

• For the initial evaluation of cognitive complaints.
• To screen cognitively normal individuals outside the context of research or clinical trials.
• When requested solely based on a family history of dementia or the presence of other Alzheimer’s disease risk factors, such as the ApoE4 gene.
• As a substitute for genetic testing for mutations that cause Alzheimer’s disease.
• For nonmedical reasons, such as insurance, legal, or employment decisions.

Finally, the criteria identify scenarios where amyloid imaging is unlikely to be useful, including as a means of determining the severity of dementia, straightforward clinical cases, and to differentiate Alzheimer’s disease from other diseases that involve the deposition of amyloid-beta.

Effects on Management and Outcomes

Relatively few studies have assessed amyloid PET’s impact on clinical decision making and patient outcomes, Dr. Rabinovici said. In 2013, the US Centers for Medicare and Medicaid Services (CMS) determined that there was insufficient evidence to justify reimbursement of amyloid PET and said that it would reimburse the scans for patients who enroll in studies to assess amyloid PET’s clinical utility, under a mechanism called coverage with evidence development. For CMS to reconsider its coverage decision, studies must demonstrate that amyloid PET changes patient management in the short term and improves dementia outcomes long term. The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which Dr. Rabinovici chairs, is a multisite study to assess the utility of amyloid PET in Medicare beneficiaries age 65 and older who meet appropriate use criteria for amyloid imaging.

The IDEAS study enrolled more than 18,000 participants and finished recruiting patients this year. It aims to examine how the scans affect patient management plans at three months and medical outcomes at 12 months. “The primary hypothesis is that, in these diagnostically uncertain cases, knowing the amyloid result will change management, and that will translate into better outcomes,” Dr. Rabinovici said.

Results regarding amyloid PET’s influence on patient management at three months will be presented soon, and 12-month outcome data are expected to be presented in 2019.

An interim analysis of the first 3,979 patients found that, three months after the amyloid PET scans, patients’ management plans had changed from the pre-PET management plan in about 67% of cases. Changes included starting or stopping Alzheimer’s-disease-specific medications and other neurologic therapies and changes in patient counseling.

Matched With Controls

To assess 12-month outcomes, investigators plan to use Medicare claims data to compare medical outcomes for patients enrolled in the study with those for matched controls who did not undergo amyloid PET. The primary objective is to determine whether amyloid PET is associated with a 10% or greater reduction in hospitalizations and emergency room visits. The researchers plan to use an algorithm to match each IDEAS study participant with a control with a similar dementia diagnosis, pre-scan dementia-related resource utilization, age, race, gender, ethnicity, geographic location, and comorbid chronic conditions.

Further imaging advances, such as tau PET tracers, are in development but have not yet received regulatory approval from the FDA, Dr. Rabinovici said. Tau PET has the potential to detect pathology in tauopathies such as progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and subtypes of frontotemporal dementia, as well as Alzheimer’s disease, he said.

—Jake Remaly

Suggested Reading

Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.

Johnson KA, Minoshima S, Bohnen NI, et al. 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. Alzheimers Dement. 2013;9(1):e1-e16.

LOS ANGELES—Amyloid PET scans may play an important role in neurologists’ management of patients with cognitive impairment. For the moment, clinical use should be restricted to cases that can be summarized with the mnemonic MAY—Mild, Atypical, and Young, said Gil D. Rabinovici, MD. “Those are the people who are most likely to benefit,” he said.

Although amyloid PET scans may affect diagnostic certainty and influence treatment in these scenarios, most patients do not get the scans. “They cost thousands of dollars, and most insurance will not pay for them,” Dr. Rabinovici said in a lecture at the 70th Annual Meeting of the American Academy of Neurology.

Looking to the future, amyloid PET may play a larger role in clinical practice if insurance providers more readily cover the cost of the scans and if the definition of Alzheimer’s disease shifts from a clinical basis to a biologic one. Someday, neurologists may be able to offer interventions to delay or prevent the onset of dementia in patients at risk of Alzheimer’s disease, Dr. Rabinovici said.“During the coming decade, we are going to see a real paradigm shift,” he said, “from the current status quo where we are diagnosing and treating clinical dementia to a paradigm where we are doing early screening with biomarkers.” Dr. Rabinovici is the Edward Fein and Pearl Landrith Distinguished Professor in the Memory and Aging Center at the University of California, San Francisco.

Three FDA-Approved Tracers

Three amyloid-beta tracers are FDA approved for clinical use in cognitively impaired patients—18F-florbetapir (Amyvid, approved in 2012), 18F-flutemetamol (Vizamyl, approved in 2013), and 18F-florbetaben (Neuraceq, approved in 2014).

The agents were approved on the basis of studies that found that blinded visual reads of amyloid PET scans during life accurately predicted postmortem burden of amyloid pathology in the same individuals. The scans distinguish patients with moderate or frequent neuritic plaques from those with absent or sparse neuritic plaques with a sensitivity and specificity of 80% or greater. Many scans can be categorized as positive or negative, and neurologists can quickly learn to read them, Dr. Rabinovici said.

Scans have the potential to improve the accuracy of Alzheimer’s disease diagnosis. Compared with postmortem findings, the clinical diagnosis of probable Alzheimer’s disease was accurate only 70% of the time in one study. Conversely, another study found that approximately 40% of patients with a diagnosis of non-Alzheimer’s disease dementia turned out to have Alzheimer’s disease as the primary causative pathology at autopsy.

Real-Life Ramifications

To illustrate amyloid PET’s potential usefulness in clinical practice, Dr. Rabinovici described a case of a 57-year-old internist. The patient had progressive trouble finding words, but otherwise did not have major symptoms or concerns. He did poorly on repeating sentences, but the rest of his examination was normal. MRI revealed nothing remarkable.

“That is the typical standard of care that is meant for someone with a cognitive complaint,” Dr. Rabinovici said. An FDG-PET scan was suspicious but not definitive. The patient’s amyloid PET scan, however, was clearly positive and showed amyloid throughout the neocortex. “With the scans, I could diagnose him. He had mild cognitive impairment, but I thought with high likelihood due to Alzheimer’s disease.”

As a result, Dr. Rabinovici started the patient on a cholinesterase inhibitor, and the patient decided to retire early due to medical disability. In addition, the patient enrolled in a clinical trial of an investigational antiamyloid therapy.

“I was not able to cure or modify the course of his Alzheimer’s disease, but amyloid PET did have real ramifications for his life,” he said.

 

Consider the Clinical Context

As with any diagnostic agent, clinical context is critical for interpreting the significance of positive and negative amyloid scans, Dr. Rabinovici said.

Among patients with dementia, amyloid PET can distinguish Alzheimer’s disease from conditions that do not involve amyloid-beta deposition, such as frontotemporal dementia or pure vascular dementia. It is not useful, however, in distinguishing Alzheimer’s disease from other conditions in which amyloid is deposited in the brain, such as cerebral amyloid angiopathy or dementia with Lewy bodies.

“It is important to consider the patient’s age when you think about the meaning of a positive scan,” he said. “A negative scan is always helpful in ruling out Alzheimer’s disease,” but a positive scan is less meaningful in older patients. Approximately 25% of cognitively normal older individuals have positive amyloid PET scans. The prevalence of amyloid positivity is about 10% at age 60 and more than 50% at age 90.

Not everyone with amyloid deposition has or develops Alzheimer’s disease dementia or mild cognitive impairment, but amyloid is a risk factor, said Dr. Rabinovici. “To summarize 15 years of research in one bullet point, it is not good to have amyloid in your brain even if you are cognitively normal,” he said. “Amyloid-positive normal controls are already showing Alzheimer’s-disease-like structural and functional changes in their brains. Over time, they are likely to decline cognitively. And they have an increased risk of cognitive impairment,” compared with people who are amyloid negative.

Research indicates that the deposition of amyloid plaques begins at least 15 years before the onset of cognitive symptoms, which may represent a window for early intervention, Dr. Rabinovici said.

When to Scan and When Not To

To guide clinicians in the appropriate use of amyloid PET, the Society for Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association in 2013 published appropriate use criteria for the technology. Given amyloid PET’s cost and need for nuanced interpretation, the authors determined that it should not be a first-line test in the evaluation of cognitive complaints, Dr. Rabinovici said. Rather, it should be an ancillary test ordered by subspecialists in patients who meet the following criteria:

• Have a cognitive complaint with objectively confirmed impairment.
• Have an uncertain diagnosis, with Alzheimer’s disease as a possibility, after comprehensive evaluation by a dementia expert.
• Knowledge of their amyloid-beta status is expected to increase diagnostic certainty and alter management.

The three main clinical scenarios in which amyloid imaging may be most useful include the following:

• Cases with persistent and progressive unexplained mild cognitive impairment.
• Cases with possible (rather than probable) Alzheimer’s disease who have an atypical or mixed course or significant comorbidities (eg, vascular, psychiatric, or substance abuse disorders).
• Cases with an atypically early age of onset (ie, younger than 65).

The appropriate use criteria also highlight the following scenarios in which clinical amyloid PET is considered inappropriate:

 

• For the initial evaluation of cognitive complaints.
• To screen cognitively normal individuals outside the context of research or clinical trials.
• When requested solely based on a family history of dementia or the presence of other Alzheimer’s disease risk factors, such as the ApoE4 gene.
• As a substitute for genetic testing for mutations that cause Alzheimer’s disease.
• For nonmedical reasons, such as insurance, legal, or employment decisions.

Finally, the criteria identify scenarios where amyloid imaging is unlikely to be useful, including as a means of determining the severity of dementia, straightforward clinical cases, and to differentiate Alzheimer’s disease from other diseases that involve the deposition of amyloid-beta.

Effects on Management and Outcomes

Relatively few studies have assessed amyloid PET’s impact on clinical decision making and patient outcomes, Dr. Rabinovici said. In 2013, the US Centers for Medicare and Medicaid Services (CMS) determined that there was insufficient evidence to justify reimbursement of amyloid PET and said that it would reimburse the scans for patients who enroll in studies to assess amyloid PET’s clinical utility, under a mechanism called coverage with evidence development. For CMS to reconsider its coverage decision, studies must demonstrate that amyloid PET changes patient management in the short term and improves dementia outcomes long term. The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which Dr. Rabinovici chairs, is a multisite study to assess the utility of amyloid PET in Medicare beneficiaries age 65 and older who meet appropriate use criteria for amyloid imaging.

The IDEAS study enrolled more than 18,000 participants and finished recruiting patients this year. It aims to examine how the scans affect patient management plans at three months and medical outcomes at 12 months. “The primary hypothesis is that, in these diagnostically uncertain cases, knowing the amyloid result will change management, and that will translate into better outcomes,” Dr. Rabinovici said.

Results regarding amyloid PET’s influence on patient management at three months will be presented soon, and 12-month outcome data are expected to be presented in 2019.

An interim analysis of the first 3,979 patients found that, three months after the amyloid PET scans, patients’ management plans had changed from the pre-PET management plan in about 67% of cases. Changes included starting or stopping Alzheimer’s-disease-specific medications and other neurologic therapies and changes in patient counseling.

Matched With Controls

To assess 12-month outcomes, investigators plan to use Medicare claims data to compare medical outcomes for patients enrolled in the study with those for matched controls who did not undergo amyloid PET. The primary objective is to determine whether amyloid PET is associated with a 10% or greater reduction in hospitalizations and emergency room visits. The researchers plan to use an algorithm to match each IDEAS study participant with a control with a similar dementia diagnosis, pre-scan dementia-related resource utilization, age, race, gender, ethnicity, geographic location, and comorbid chronic conditions.

Further imaging advances, such as tau PET tracers, are in development but have not yet received regulatory approval from the FDA, Dr. Rabinovici said. Tau PET has the potential to detect pathology in tauopathies such as progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and subtypes of frontotemporal dementia, as well as Alzheimer’s disease, he said.

—Jake Remaly

Suggested Reading

Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.

Johnson KA, Minoshima S, Bohnen NI, et al. 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. Alzheimers Dement. 2013;9(1):e1-e16.