Nuclear medicine

Dual-phase protocol: a two-for-one deal for brain imaging

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A novel nuclear medicine imaging protocol can take the place of two separate imaging scans for the evaluation of brain changes linked to cognitive impairment, cutting costs and radiation exposure for patients as well as providing them greater comfort.

The protocol—known as dual-phase amyloid PET—can assess both amyloid deposition and neurodegeneration with a single tracer injection, assisting physicians as they classify patients on the Alzheimer’s disease continuum. This research was published in the February issue of The Journal of Nuclear Medicine. 

This graphical Abstract shows the comparability of early-phase amyloid-PET and...

This graphical Abstract shows the comparability of early-phase amyloid-PET and FDG-PET images at the single-subject level.

Image source: SNMMI; Boccalini et al., Journal of Nuclear Medicine 2023

Alzheimer’s disease causes several changes in the brain, including neurodegeneration and beta-amyloid deposition. Currently, 18F-FDG scans are used to measure brain metabolism, which can indicate neurodegeneration. Amyloid PET scans are performed to evaluate beta-amyloid deposition, a key characteristic of Alzheimer’s disease. “During the amyloid PET scans, nuclear medicine physicians wait at least 50 minutes after the radiotracer injection to acquire the image of beta-amyloid deposition. If images are also taken immediately after injection (early-phase), they can provide a measure of brain perfusion. Since brain perfusion and brain metabolism are closely related, the perfusion information could replace an 18F-FDG PET scan,” said Cecilia Boccalini, MSc, PhD candidate at the Laboratory of Neuroimaging and Innovative Molecular Tracers and faculty of medicine at the University of Geneva Neurocenter in Geneva, Switzerland, and faculty of neuroscience at Vita-Salute San Raffaele University in Milan, Italy.

Obtaining both amyloid and perfusion data with a single tracer injection is optimal in terms of patient safety and radiation exposure, comfort, and costsValentina Garibotto

The study aimed to compare early-phase amyloid PET scans and 18F-FDG scans at the individual level, as well as their ability to distinguish patients along the Alzheimer’s disease continuum. A total of 166 patients ranging from cognitively unimpaired to mild cognitive impairment and dementia underwent 18F-FDG and early-phase amyloid PET scans. Brain hypoperfusion maps (from the early-phase amyloid PET) and brain hypometabolism maps (from 18F-FDG PET) were created and compared for each patient. 

Results showed that brain hypoperfusion assessed by early-phase amyloid PET is comparable with brain hypometabolism assessed by 18F-FDG-PET. Hypoperfusion and hypometabolism patterns were also equally able to distinguish patients with neurodegenerative diseases from controls. “This dual-phase amyloid-PET protocol allows physicians to measure brain amyloid and perfusion in a single procedure,” stated Valentina Garibotto, MD, head of the Nuclear Medicine and Molecular Imaging Division at Geneva University Hospitals in Geneva, Switzerland, and associate professor at the University of Geneva. “Obtaining both amyloid and perfusion data with a single tracer injection is optimal in terms of patient safety and radiation exposure, comfort, and costs. Our work supports the routine use of the dual-phase amyloid PET protocol in clinical practice.” 

Source: Society of Nuclear Medicine and Molecular Imaging

Targeted molecular imaging in oncology.

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Improvement of scintigraphic tumor imaging is extensively determined by the development of more tumor specific radiopharmaceuticals. Thus, to improve the differential diagnosis, prognosis, planning and monitoring of cancer treatment, several functional pharmaceuticals have been developed. Application of molecular targets for cancer imaging, therapy and prevention using generator-produced isotopes is the major focus of ongoing research projects. Radionuclide imaging modalities (positron emission tomography, PET; single photon emission computed tomography,

SPECT) are diagnostic cross-sectional imaging techniques that map the location and concentration of radionuclide-labeled radiotracers.

99mTc- and 68Ga–labeled agents using ethylenedicysteine (EC) as a chelator were synthesized and their potential uses to assess tumor targets were evaluated.

99mTc (t1/2 = 6 hr, 140 keV) is used for SPECT and 68Ga (t1/2 = 68 min, 511 keV) for PET. Molecular targets labeled with Tc-99m and Ga-68 can be utilized for prediction of therapeutic response, monitoring tumor response to treatment and differential diagnosis. Molecular targets for oncological research in (1) cell apoptosis, (2) gene and nucleic acid-based approach, (3) angiogenesis (4) tumor hypoxia,and (5) metabolic imaging are discussed. Numerous imaging ligands in these categories have been developed and evaluated in animals and humans. Molecular targets were imaged and their potential to redirect optimal cancer diagnosis and therapeutics were demonstrated.

Source: http://www.jsnm.org

 

Brain Amyloid Imaging — FDA Approval of Florbetapir F18 Injection.

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The Centers for Disease Control and Prevention recently estimated that more than 16 million Americans are living with cognitive impairment.1 Cognitive impairment can be ascribed to a variety of disorders, some of which can be treated (e.g., severe depression or effects of medications) but others of which may signal the development of incurable dementias, such as Alzheimer’s disease. For these reasons, the development and improvement of diagnostic procedures — and neuroimaging procedures, in particular — that aid in characterizing cognitive impairment is a health care priority. Improved diagnostic evaluation of patients with cognitive impairment may also enhance the development of therapies, since reliable diagnoses are critical to the success of clinical trials.

Recently, the Food and Drug Administration (FDA) approved a new radiopharmaceutical agent to assist clinicians in detecting causes of cognitive impairment other than Alzheimer’s disease. Florbetapir F18 injection (Amyvid, Eli Lilly) is indicated for positron-emission tomographic (PET) imaging of the brain in cognitively impaired adults undergoing evaluation for Alzheimer’s disease and other causes of cognitive decline.2 Florbetapir binds to amyloid aggregates in the brain, and the florbetapir PET image is used to estimate the density of β-amyloid neuritic plaque. As a component of a comprehensive diagnostic evaluation, the finding of a “negative” florbetapir scan (as qualified below) should intensify efforts to find a non–Alzheimer’s disease cause of cognitive decline. Florbetapir brain imaging is a new type of nuclear medicine imaging, and the interpretation of the image requires special training. The unique features of the imaging information also require careful consideration when the scan results are integrated into a diagnostic evaluation.

Although the pathophysiological consequences of accumulation of β-amyloid in the brain are uncertain, neuropathological identification of amyloid plaques, typically at autopsy, has long been recognized as essential to confirming the diagnosis of Alzheimer’s disease. Because β-amyloid plaques in the brain have been described as a “hallmark” of Alzheimer’s disease, some clinicians may regard the florbetapir scan as a new test for the disease.3 But the drug was developed exclusively to estimate the density of β-amyloid neuritic plaque in the brain, and these plaques have been detected in patients with a variety of neurologic disorders, as well as in older people with normal cognition (see Florbetapir F18 Scan Usage: Information Summary).

Florbetapir is an 18F-labeled ligand that, in nonclinical studies, was shown to bind to β-amyloid aggregates in postmortem sections of human brains and in brain homogenates.4 In the main clinical studies supporting FDA approval, the accuracy of florbetapir scans was assessed in the brains of terminally ill patients who participated in a brain-donation program. The patients, who had a range of underlying cognitive function, underwent florbetapir scans and were followed until they died. The premortem scan results were subsequently compared with the brain autopsy findings. In all the clinical studies, the florbetapir scans were independently interpreted by multiple readers who had completed training in interpreting florbetapir images.

A binary method of interpretation was developed for relating “positive” or “negative” florbetapir scans to neuropathologically defined categories of density of β-amyloid neuritic plaque. The method designated a positive florbetapir scan as categorically indicative of “moderate to frequent” β-amyloid neuritic plaques, as defined by the consensus criteria for Alzheimer’s disease neuropathology established by the National Institute on Aging. In 59 patients who underwent florbetapir scans and autopsy, scan sensitivity for the detection of moderate to frequent β-amyloid neuritic plaques was 92% (range, 69 to 95), and scan specificity was 95% (range, 90 to 100), on the basis of the median assessment among five readers (ClinicalTrials.gov number, NCT01447719).

One of the challenges of the florbetapir clinical development program was that terminally ill patients are not representative of the population that is likely to undergo florbetapir scanning in medical practice. In addition, β-amyloid content could change between the time of live brain imaging and the time of autopsy. More than 20% of autopsies in the main clinical studies were performed more than a year after the live brain imaging (NCT01447719 and NCT01550549).

To evaluate scan reliability in a wider population, a clinical study had new readers examine images from non–terminally ill patients with Alzheimer’s disease or mild cognitive impairment, as well as persons with normal cognition. The previously obtained images from autopsied patients were also included in the study (NCT01550549). Among five readers who interpreted images from the 151 subjects, the kappa score for interrater reliability was 0.83 (95% confidence interval, 0.78 to 0.88), with the lower bound of the 95% confidence interval exceeding the prespecified reliability success criterion of 0.58. For the autopsy subgroup of 59 subjects, the median scan sensitivity was 82% (range, 69 to 92), and the median scan specificity was 95% (range, 90 to 95) for the five new readers.

Clinical and nonclinical studies verified that florbetapir scans can provide neuropathologically accurate and reliable estimations of the density of β-amyloid neuritic plaque in the brain. Nevertheless, as with other imaging methods, there is potential for clinical interpretive error. In the studies of scan accuracy, such errors were uncommon but when present were due mainly to false negative results, as determined by the density of β-amyloid neuritic plaque at autopsy.

Reader training was an especially important element in the clinical development of florbetapir, because the image-interpretation process differs markedly from that typically used in nuclear medicine. For example, the image reader must be proficient in distinguishing white from gray matter, a distinction that may be particularly challenging in patients with cortical atrophy. Unique “gray–white contrast” characteristics of florbetapir images must be recognized as signals of normal or abnormal isotope distribution (see figureTypical Negative and Positive Florbetapir Scans.). In addition, cognitive status and other clinical or diagnostic information are not considered during the interpretation of florbetapir images. The sole goal of the reader is to determine whether a scan is negative or positive, and this determination should be made only by readers who have completed the sponsoring company’s dedicated training program. The success of the reader-training process will be further evaluated in a postmarketing study of image interpretations performed under the typical conditions of clinical practice.

In approving florbetapir, the FDA did not require clinical data assessing the effect of florbetapir imaging on clinical management or patients’ health. The FDA code of regulations (in 21 CFR 315.5[a]) mandates that the effectiveness of a diagnostic radiopharmaceutical agent should be determined by an evaluation of the ability of the agent to provide useful clinical information related to the proposed indications for use. FDA guidance further recognizes that imaging information may in some instances “speak for itself” with respect to clinical value5 and that diagnostic approval may therefore not require assessment of the effects on clinical management or health outcomes. Two FDA advisory committees endorsed the implicit clinical value of information obtained from brain β-amyloid imaging. Florbetapir approval was based on this endorsement and on clinical data showing sufficient scan reliability and performance characteristics.2

The ultimate clinical value of florbetapir imaging awaits further studies to assess the role, if any, that it plays in providing prognostic and predictive information. For example, 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 responses to medication. These concerns prompted the FDA to require a specific “Limitations of Use” section in the florbetapir label.

The FDA approval of florbetapir F18 injection sets the stage for future studies that increase the value of the technique in addressing the diagnostic challenges associated with cognitive impairment. Further investigation of the drug in the postmarketing context is consistent with the commitment of the FDA to the development of imaging products that aid in the diagnostic evaluation of cognitively impaired patients.

Florbetapir F18 Scan Usage: Information Summary.

A negative florbetapir scan:

• indicates sparse to no neuritic plaques.

• is inconsistent with a neuropathological diagnosis of Alzheimer’s disease at the time of image acquisition.

• reduces the likelihood that a patient’s cognitive impairment is due to Alzheimer’s disease.

A positive florbetapir scan:

• indicates moderate to frequent amyloid neuritic plaques.

• may be observed in older people with normal cognition and in patients with various neurologic conditions, including Alzheimer’s disease.

Important florbetapir scan limitations:

• A positive scan does not establish a diagnosis of Alzheimer’s disease or other cognitive disorder.

• The scan has not been shown to be useful in predicting the development of dementia or any other neurologic condition, nor has usefulness been shown for monitoring responses to therapies.

References

  1. 1

Promoting brain health. Atlanta: Centers for Disease Control and Prevention, 2011 (http://www.cdc.gov/aging/pdf/cognitive_impairment/cogImp_genAud_final.pdf).

  1. 2

Highlights of prescribing information: Amyvid (florbetapir F18 injection). Silver Spring, MD: Food and Drug Administration (http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202008s000lbl.pdf).

  1. 3

Okie S. Confronting Alzheimer’s disease. N Engl J Med 2011;365:1069-1072
Full Text | Web of Science | Medline

  1. 4

Lister-James J, Pontecorvo MJ, Clark C, et al. Florbetapir F-18: a histopathologically validated beta-amyloid positron emission tomography imaging agent. Semin Nucl Med 2011;41:300-304
CrossRef | Web of Science

  1. 5

Guidance for industry: developing medical imaging drug and biological products. Part 2: clinical indications. Washington, DC: Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, 2004 (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071603.pdf).

 

Source: NEJM