Abstract
Alzheimer disease (AD) is the sixth leading cause of death in the United States and is projected to affect over 13 million people by the year 2060. Although there is currently no cure for AD, disease-modifying treatments that target amyloid plaques have recently been approved for use. The advent of PET tracers that can reliably detect the presence of cortical amyloid plaques and tau pathologies has allowed researchers and clinicians to identify individuals who have pathologic markers of AD before the onset of cognitive decline. Although these tracers have been widely used in research settings for some time, they are now on the verge of being used to aid clinicians in the differential diagnosis of AD. As the use of these tracers increases, technologists will need to be educated on the best practices and potential problems they may encounter in their clinical populations. This article will review the available tracers for amyloid and tau PET scans and educate technologists about the most important practices and procedures that can be implemented to ensure patient safety and the capture of high-quality scans.
OVERVIEW OF ALZHEIMER’S DISEASE (AD)
AD is a progressive neurodegenerative disorder that primarily affects memory, thinking, and behavior. AD is the most common type of dementia, constituting approximately 60%–80% of all dementia cases (1). AD can be considered a terminal illness as affected individuals have a progressive decline in cognition and daily function over time. Symptomatic treatments with modest benefits have been available since the 1990s; however, disease-modifying therapies have become available in the last few years (2).
In the United States, it is estimated that 6.9 million individuals have AD, which could double by 2050 (1). AD is currently the sixth leading cause of death in the United States and is the fifth leading cause among individuals aged 65 and older. Black and Latino individuals have a higher risk of AD than do their Caucasian counterparts, and women comprise more than two thirds of all AD cases in the United States.
Individuals diagnosed with AD are predominantly cared for by family members or friends, and it is estimated that 11 million individuals provide an estimated $350 billion in unpaid care to those affected by AD. The total lifetime cost of caring for someone with AD is estimated to be $400,000.
Neuropathology of AD
Dr. Alois Alzheimer, for whom AD is named, is credited with discovering the underlying pathology that is characterized by the presence of amyloid plaques (APs) and tau-based neurofibrillary tangles (NFT) (Fig. 1) (3). Current treatment approaches have focused on the removal and prevention of AP pathology. They are based on the amyloid cascade hypothesis, which posits that the deposition of APs marks the beginning of the biologic disease process for AD, leading to the formation of NFTs and, eventually, cognitive decline (4). Although many scientists and clinicians support the amyloid cascade hypothesis (5), a great deal of evidence demonstrates that AP pathology weakly correlates with cognitive decline (6). In contrast, NFT pathology tends to show stronger correlations with cognition in AD (7). It is important to note that the amyloid cascade hypothesis does not propose a mechanism for how APs develop; however, evidence suggests that inflammatory and cardiovascular factors might be responsible for the initial formation of APs (8).
Alzheimer neuron. AD is characterized by abnormal deposition of APs and NFTs. APs found between nerve cells are amorphous clumps of amyloid-β protein along with neuron and other cell fragments. NFTs found within neurons are bundles of twisted tau filaments.
APs are made up of aggregated amyloid proteins that result from deficient amyloid clearance mechanisms in the brain. There are 2 forms of APs, neuritic plaques and diffuse plaques (Fig. 2). Neuritic plaques have a dense core of neuritic material surrounded by amyloid accumulation and are associated with decreased cognitive performance (9). Diffuse plaques are amorphous accumulations of amyloid that do not have a dense core and are thought to be age-associated, but they also frequently occur in those with AD.
Postmortem AP types. (A) Diffuse plaques have unstructured shape and no dense core. (B) Neuritic plaques, also called senile or dense plaques, are characterized by neuronal material surrounding amyloid-β deposits. Modified from (18); images courtesy of UCSF Neurodegenerative Disease Brain Bank.
NFTs are aggregated tau proteins resulting from the demyelination and breakdown of axons after neurons are compromised. Standardized measures to quantify the degree of AP and NFT pathology were developed in the 1990s and are still widely used. The Consortium to Establish a Registry for Alzheimer Disease is a semiquantitative scale of neuritic plaque density that uses a scale of 0–3 that corresponds to no neuritic plaques, sparse neuritic plaques, moderate neuritic plaques, and frequent neuritic plaques, respectively (10) (Fig. 3).
Consortium to Establish a Registry for Alzheimer Disease scale. Semiquantitative measurement of neuritic plaque (NP) density: sparse plaques (A), moderate plaques (B), and frequent plaques (C). Modified from (18); images courtesy of UCSF Neurodegenerative Disease Brain Bank.
The Thal amyloid stages indicate the degree of diffuse plaque deposition in specific regions of the brain using a 5-stage scoring scheme (stage 1, neocortex; stage 2, allocortex/limbic; stage 3, diencephalon/basal ganglia; stage 4, brain stem/midbrain; stage 5, cerebellum) (11) (Fig. 4).
Thal phases of amyloid-β (Aβ) plaque accumulation and corresponding clinical status. (A) Phase 0: no AD or non-AD dementia. (B) Phases 1–3: pre-AD or non-AD dementia. (C) Phases 4 and 5: symptomatic AD. Adapted under CC-BY license from (19).
NFT pathology is quantified using the Braak staging system, which has 6 stages based on where NFT depositions occur (stages I and II, transentorhinal; stages III and IV, limbic regions; stages V and VI, neocortex) (12) (Fig. 5).
Braak stages of NFT disposition. Sagittal slices of brain at midline with affected brain regions in shades of purple. (A) Stage 0: no tau accumulation. (B) Stages I and II: transentorhinal (arrow, small deposition). (C) Stages III and IV: limbic. (D) Stages V and VI: isocortical. Modified with permission from (20).
Although high levels of APs and NFTs are usually found in individuals with clinical AD, it is also known that a large proportion of cognitively unimpaired individuals have significant levels of AP and NFT pathology without demonstrating any cognitive impairment (13). There is increasing interest in studying these individuals who are thought to have preclinical AD. Current research and treatment paradigms focus on identifying preclinical AD and initiating disease-modifying interventions that significantly slow or completely prevent the onset of significant cognitive and functional decline (14).
Clinical Features and Symptoms
The hallmark clinical features of AD are progressive memory loss followed by a decline in one or more additional cognitive domains such as attention, language, visuospatial function, and executive function (15). The prodromal state of AD, amnestic mild cognitive impairment, indicates that only memory is impaired with other cognitive domains remaining intact (16). Commonly reported cognitive symptoms in amnestic mild cognitive impairment include repeating stories, statements, and questions; trouble knowing the day, date, month, and year; difficulty in managing finances; and decreased sense of direction (17).
Clinical Assessment
The clinical diagnosis of AD often begins with a report of significant memory loss to a general practitioner, who then refers the individual to memory disorder specialists for a full diagnostic work-up. AD is often diagnosed through the exclusion of other possible factors that could be causing the reported memory problems (e.g., stroke, tumor, depression, vitamin deficiency).
A neuropsychological examination that assesses an individual’s age- and education-normative performance in different cognitive domains is often used to aid in the diagnosis. The neuropsychological examination yields an individual’s cognitive performance profile that can then be used to determine whether their cognitive deficits are consistent with a particular diagnosis (e.g., AD vs. frontotemporal dementia) (15). Although an exclusionary process is still the predominant approach to making a clinical diagnosis of AD, recent advances in neuroimaging and blood biomarker assessments will soon make AD easier to detect earlier and diagnose more accurately.
ROLE OF NEUROIMAGING
MRI has been the most widely used neuroimaging modality in both clinical and research settings for AD; however, advances in PET techniques now allow for the AP and NFT pathology of AD to be detected and measured without the need for autopsy or biopsy of brain tissue. Although MRI is often used to rule out other possible causes of cognitive decline, the ability to detect the underlying pathology of AD through PET scans allows clinicians to be more confident in their diagnoses. Although PET is not yet widespread in clinical settings for diagnosing AD, recent regulatory decisions have paved the way for these measures to be implemented on a large scale and to become routine in the diagnostic process for AD.
Amyloid PET Imaging
The first notable agent, developed over 2 decades ago at the University of Pittsburgh, is Pittsburgh Compound B (PiB). It was a major advancement in the field in allowing for in vivo assessment of amyloid-β deposition. Although PiB provided excellent image resolution and differentiated AD patients from non-AD subjects, its reliance on the short-lived isotope 11C limited its commercial use.
The second amyloid tracer, but the first to gain Food and Drug Administration (FDA) approval, was 18F-AV45, commonly known as Amyvid (Eli Lilly and Company), which was approved in 2012. This tracer used a more stable isotope, which allowed for broader commercialization, unlike 11C-PiB, which has a short half-life of 20 min and requires a nearby cyclotron for production. In 2013, another tracer,18F-flutemetamol, branded as Vizamyl (GE HealthCare), was approved, further expanding the options available for detecting APs in the brain. In March 2014, 18F-florbetaben, known as Neuraceq (Life Molecular Imaging), also obtained FDA approval, adding to the growing collection of diagnostic amyloid tracers. Currently, the 3 FDA-approved amyloid tracers on the market are 18F-AV45, 18F-florbetaben, and 18F-flutemetamol. Additionally, 18F-NAV4694, is currently in phase III development. There are 2 non–FDA-approved amyloid tracers, 11C-PiB and 18F-NAV4694, considered for investigational use only.
Tau PET Imaging
Tau PET imaging has emerged as a crucial tool for diagnosing and understanding neurodegenerative diseases, with 18F-AV1451 (Tauvid; Eli Lilly and Company) currently the only FDA-approved tracer that detects cortical tau deposits. To ensure consistent and accurate results, following standardized protocols for tracer administration and imaging, is vital. Typically, tau PET scans are conducted 75–90 min after injection, with the scanning process lasting around 30 min.
In addition to Tauvid, several other tau tracers, such as 18F-MK6240, 18F-GTP1, and 18F-PI2620, are being studied under an Investigational New Drug protocol. However, Tauvid remains the only tracer with FDA approval, which was granted in May 2020.
RESEARCH CONSIDERATIONS AND BEST PRACTICE TIPS
Before a participant is scanned, research protocols must be submitted to and approved by an institutional review board or ethics committee, which typically requires signed written informed consent. The institutional review board reviews research protocols to safeguard the rights and welfare of human research participants by ensuring ethical conduct and proper informed consent procedures. In addition, any research protocol that involves the use of ionizing radiation, like x-rays or radioactive materials, must be submitted to and approved by the Radiation Safety Officer before scanning can begin. Our primary responsibilities center around the radioactive materials license, ensuring it is current and permits the administration of PET tracers to human research subjects. Ethical considerations and patient consent are paramount in AD imaging research. Participation in research is entirely voluntary, and we prioritize informing patients about the scanning process and its implications. If a patient is claustrophobic without resolution or chooses to withdraw from a study, we respect their decision without hesitation and acknowledge their autonomy and right to participate.
Research participants periodically undergo PET imaging to evaluate the efficacy of experimental treatments to remove APs and tau tangles over time. To obtain FDA approval for new radiopharmaceuticals, it is essential to demonstrate their binding specificity, which is often validated using postmortem autopsy data to compare antemortem imaging results with postmortem brain tissue samples.
Protocol Adherence
When initiating a new research study, a PET technologist must build the protocol on the scanner that strictly adheres to the research study’s protocol. The sponsor or investigator for a research study will send a specification sheet with the camera parameters that are desired for a study. Once the protocols are built, imaging centers are often required to send screenshots and a mock phantom scan to double check the header information. Once approval is received from the sponsor, the imaging center can begin scheduling research participants.
If an imaging center has multiple PET cameras, it is crucial to track which participant is assigned to each camera to ensure accurate and consistent comparisons, considering the differences between manufacturers and models. For longitudinal studies, follow-up scans should be conducted on the same camera that was used for the initial baseline or screening. If the original camera is unavailable, consult with the study sponsor to approve using another camera or consider rescheduling the scan. Close collaboration with clinical research coordinators can facilitate the effective scheduling of participants and help meet study deadlines. An organized dose-tracking system is required to preserve detailed documentation for each tracer received at the imaging facility. This includes documenting the date and time of receipt, batch and syringe IDs, the dates and times of injection and disposal, subject identification, and the initials and date of the completing technologist.
During the imaging visit, verifying the completeness and accuracy of all subject demographic and exam information on the PET transmittal forms is essential. This ensures compliance with privacy regulations that protect subject confidentiality. The administration process is critical for PET technologists, necessitating thorough documentation throughout the imaging process.
It is essential to place a high-quality intravenous line, as these radiopharmaceuticals can be quite expensive, costing thousands of dollars to produce. Additionally, complete tracer administration is crucial for achieving an accurate and reliable scan. After the dose is preassayed and injected, a residual postassay is necessary to confirm the total net injected dose. Tracers are injected precisely at the top of the minute, and scans are started at the top of the minute. Most research protocols permit only a ±1-min deviation from the planned scan time. During scanning, it is important to gather comprehensive data as effective research entails not only capturing accurate images but also collecting supporting data that enhances the validity of our findings.
Adverse Events (AEs)
Technologists are responsible for assessing any AEs or serious AEs that may occur after the tracer injection, highlighting the unique challenges and responsibilities faced in research PET imaging. For PET technologists working in a research setting, it is crucial to understand the safety protocols, AE reporting, and regulatory compliance associated with investigational products.
Unlike commercially approved tracers, PET imaging facilities using investigational tracers must adhere to local Investigational New Drug requirements. This includes maintaining an Investigational Medicinal Product log and monitoring subjects for any AEs during their visit to the imaging facility.
An AE can be any unfavorable and unintended signs, symptoms, or abnormal laboratory findings linked to the medical treatment or procedure, irrespective of their relation to the tracer used. After tracer injection, following the manufacturer’s instructions for AE monitoring is essential. The principal investigator at the clinical site bears the responsibility of reporting AEs per the study protocol to the sponsor. Although AEs are not expected to occur often, prompt communication with the clinical study site personnel, such as the principal investigator or study coordinator, is vital if any AEs arise during imaging. It is also essential to document the time and details of any calls made regarding AEs and archive the original documents in local records.
Finally, all study data must be maintained for the study duration and retained for a duration mandated by local or federal regulations. Understanding and adhering to these protocols ensures the subjects’ safety and the research process’s integrity.
Patient Positioning
Patients must be properly positioned to ensure that the entire brain, including the complete cerebellum, is within the field of view. The patient’s head must have the chin tucked slightly so the orbitomeatal line is 90° to the imaging bed, as shown in Figure 6.
Proper positioning of orbitomeatal line at 90° angle to floor. Alignment ensures frontal lobe is adequately positioned, preventing head from tilting back and avoiding clipping of frontal lobe during imaging. Adapted from (21).
Patients with mobility issues may have difficulty tucking their chin. In contrast, other patients will tuck more than is necessary. Having a head holder and placing sponges to help tuck the chin toward the neck can be helpful. Kyphotic patients may be unable to lay their heads back onto an imaging table or head holder. Having the subject sit on a pillow or 2 before lying down can help them place their head in the holder. This step often requires 2 technologists to ensure correct positioning. In addition, placing a pillow under an individual’s posterior relieves pressure on their neck as it allows their head to be comfortably placed into the support of the head holder.
Timing and Scheduling
Maintaining strict adherence to the required timing of tracers and scans can make conducting research studies challenging. One practice that can be helpful is to look up and record each subject’s incubation and scan time on the day before the scan, which can save much-needed time on the day of the scan. When multiple patients are scheduled, it is helpful to determine what the minimum time can be between injections on the day before the scan. Additional considerations include incubation time, time to prepare and position the patient, scan time, and time for cleaning and preparing the imaging table for the next patient.
Quality Control
Quality control procedures ensure reliable data acquisition in PET imaging. The accuracy of PET source data relies heavily on the optimal performance of the PET scanner, dose calibrators, and other supporting equipment. To sustain a high level of performance, it is essential to conduct regular quality control checks, including daily CT tests, daily PET scans, detector calibrations, 3-dimensional norms, and well-counter cross-checks, as recommended by the equipment manufacturer. Promptly notify a field service engineer of any damage or issues with the camera or scan quality, as such problems can lead to inaccurate data.
Data Management
Research scans should be uploaded electronically within 24 h or as the study sponsor instructs. Although uploading is the most efficient option, sending the scan through the mail is permissible in some instances. To maintain subject confidentiality, names, personal identifiers, and other identifying information, such as social security and medical record numbers, should not be included in the electronic header. The identifiers often used for research subjects are study site number, subject number, and birth year.
Research Challenges with AD Population
Obtaining research PET scans with the AD population presents numerous challenges. Having a study partner present for the entire procedure duration is incredibly beneficial. The study partner is usually someone familiar to the participant and can assist in maintaining their focus and adhering to instructions. Given that these tracers require long incubation periods, patients need to understand the purpose of their presence. The involvement of a study partner can significantly help impaired participants avoid wandering and becoming disoriented and agitated.
Technologists frequently find themselves reiterating and repeating instructions because of the memory impairment associated with AD. Recognize that these difficulties in following directions are not a matter of willful noncompliance but a consequence of the patient’s illness. Therefore, technologists must be patient and understanding, acknowledging that these individuals grapple with an uncontrollable disease that impairs their memory and comprehension.
CONCLUSION
Each of the steps outlined in this article contributes to the overall success of the imaging study by reinforcing the importance of best practices in achieving reliable and accurate results. By focusing on these ethical considerations and research tips, technologists can enhance the integrity of AD imaging research. Understanding and being aware of the various technical and logistical challenges of PET imaging in AD research will allow technologists to contribute valuable insights that will help advance the understanding of AD.
DISCLOSURE
This work was supported by Arizona Alzheimer’s Disease Research Center (P30AG072980-04); APOE in the Predisposition to, Protection from and Prevention of Alzheimer’s Disease (R01AG069453-04). No other potential conflict of interest relevant to this work was reported.
Footnotes
CE credit: For CE credit, you can access the test for this article, as well as additional JNMT CE tests, online at https://www.snmmilearningcenter.org. Complete the test online no later than December 2027. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 80% of the questions correctly to receive 1.0 CEH (Continuing Education Hour) credit. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certificate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test.
Published online Nov. 12, 2024.
REFERENCES
- Received for publication October 3, 2024.
- Accepted for publication October 15, 2024.
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