Continuing Education Activity

A brain PET (positron emission tomography) scan is a highly sensitive nuclear medicine imaging technique that maps the distribution of radiopharmaceuticals in physiological and pathological conditions. This activity describes the process of obtaining a brain PET scan and reviews the current clinical use of neuro PET assessments by the interprofessional team.

Objectives:

• Summarize the PET acquisition process.
• Review the different radiopharmaceuticals used in neurology-related PET.
• Outline the impact of amyloid PET imaging on neurodegenerative outcomes.
• Describe the importance of using F18 Fluorodopa (FDOPA) by the interprofessional team in the evaluation of movement disorders.

Introduction

Brain positron emission tomography (PET) scans provide functional assessments of different physiological and pathophysiological cerebral changes. PET scans allow us to clinically visualize glucose or amino acid metabolism, dopamine receptors, as well as amyloid and tau deposits in the brain. PET imaging in the context of neuroimaging is used to evaluate tumors, infection, inflammation, various neurodegenerative processes, and seizure disorders. The range of pathologies that can be evaluated for in PET neuroimaging has been gradually growing with new radiotracers showing promise in evaluating diseased brain tissue. [1]

Anatomy and Physiology

Various radiotracers act by targeting and localizing to specific biological and physiological processes in the body. [2] Every radiotracer contains a radioisotope and a biochemical compound. The biochemical compound essentially acts by localizing to a specific target. These compounds are present in radiopharmaceuticals in trace levels and hence are called radiotracers. These radiotracers have no pharmacological effect because the active compound is present at trace levels. While radiotracers act to localize to tissue, a radioisotope, on the other hand, allows us to capture an image.

For glucose metabolism evaluation, F18 Fluorodeoxyglucose (FDG) is typically used. FDG normally biodistributes to the entire cerebral and cerebellar cortical structures. It also maps subcortical structures such as the thalami and basal ganglia. FDG enters the cell through glucose transporters (GLUT), mainly GLUT1. [3] It is then phosphorylated by hexokinase and trapped in the cell. It is important to note that FDG does not go metabolic breakdown through the Krebs cycle. FDG uptake is proportional to the upregulation of GLUT transporters and hexokinase activity. On the other hand, amino acid imaging of the brain uses F18 Flourodopa (FDOPA). FDOPA crosses the blood-brain barrier and enters the cell through large neutral amino acid transporters (LAT). [4] 

FDOPA is converted to fluorodopamine by a dopa decarboxylase enzyme. [5] LAT transporters and dopa decarboxylase activity are upregulated in brain tumors resulting in increased FDOPA uptake. FDOPA also biologically accumulates and is stored in the presynaptic dopaminergic nerve terminals of the basal ganglia structures. This latter allows us to evaluate dopamine metabolism in movement disorders. Additionally, three amyloid imaging PET agents are FDA approved to evaluate amyloid buildup in the brain. Either F18 florbetapir, F18 flutemetamol, or F18 florbetaben can be used to evaluate qualitatively, and quantitatively amyloid neuritic plaque density. After injection, these radiotracers will bind to cortical beta-amyloid plaques. Tau deposition in the brain is another hallmark of certain neurodegenerative diseases. Tau neurofibrillary tangles can be evaluated qualitatively and quantitatively using the FDA-approved radiotracer. [6]

Indications

A variety of conditions can be assessed using brain PET scans:

• Differentiating frontotemporal dementia from Alzheimer's disease (AD) [7]
• Differentiating several neurodegenerative conditions by molecularly phenotyping patients using a combination of radiotracers
• Differentiating tremors related to parkinsonian versus non-parkinsonian syndromes [8]
• Evaluating the severity of disease in neurodegenerative conditions and movement disorders
• Evaluating the seizure onset zone in medically refractory epilepsy
• Diagnosing encephalitis [9]
• Localizing the site of infection such as in the setting of encephalitis
• Evaluating brain tumor prognosis
• Defining the optimal site in preparation of biopsy (e.g., site of maximum tracer uptake)
• Delineating tumor extent for surgery and radiotherapy planning
• Differentiating glioma recurrence from treatment-induced changes, e.g., pseudoprogression, radionecrosis
• Differentiating tumor response from the pseudo-response during antiangiogenic therapy
• Intraoperative navigation for brain tumor resection [10]

Contraindications

No definite contraindications exist to the performance of a brain PET scan. Only unindicated studies would be inappropriate to perform as they may confuse the clinical picture. They would also incur to the patient unnecessary radiation exposure, albeit small. Close attention as to the need for the study should be performed with greater caution in the pediatric population.

Equipment

Today, most PET scanners are hybrid-imaging devices and are traditionally coupled to a computed tomogram (CT) scanner in a single gantry or, less commonly, to magnetic resonance imaging (MRI). PET scans acquire data from patients injected with different radiopharmaceuticals. PET scans contain crystals that will interact with photons emitted from the patient. [11] The origin of these photons in the patient’s body is deducted through advanced computer circuitry, and an image is reconstructed. This image will provide information on the biodistribution of the radiopharmaceutical in the specific patient at the time of injection. 

Personnel

Nuclear medicine technologists are intimately involved in the acquisition of PET scans. They represent qualified personnel and have been trained in radiation safety practices and elements related to safe and effective use, quality control, and handling of radiopharmaceuticals. They are also qualified in the acquisition of PET imaging and proper reconstruction. They are trained in the proper application of the PET scanner machine. Depending on the institutional policy, they are frequently also responsible for intravenous access.

Preparation

Patients need to be well hydrated before neuroimaging PET scans. When FDG is used, patients need to be fasting for 4-6 hours before the study. They also need to avoid sedatives before the uptake phase. Administration of sedatives or anxiolytics can occur after at least 30 minutes post-injection of the radiotracer. Patients usually need to be in a quiet, dimly lit room for the uptake phase. No special preparation is required before tau and amyloid PET imaging. Some reports have suggested avoiding a diet rich in proteins immediately before FDOPA scans, although this is not standard. Adequate hydration following the scans to help excrete the radiotracer is recommended.

Technique

Following intravenous access and the injection of the appropriate radiopharmaceutical, an uptake phase occurs. During the uptake phase, the radiotracer will biodistribute to its intended target and wash out from background tissues, allowing optimal imaging. Uptake times vary based on the radiotracer and indication. The PET radiopharmaceutical is a positron emitter and, once injected, will biodistribute in tissues where it will interact with electrons. This interaction phenomenon is called an annihilation phenomenon, as the positron will annihilate with the electron and produce two 511 KeV photons that travel in two opposite directions at 180 degrees. [12] These photons will interact on their end with the PET crystal and the subsequent production of the PET image.

Complications

As PET scans use small amounts of radioactive compounds, there is a minimal amount of radiation exposure. The concern occurs with multiple repeated scans. Radiation exposure is of most concern in pregnant women and very young children. Following the radiotracer injection, patients may experience some discomfort at the injection site and bruising from the intravenous cannulation process.

Radiotracer extravasation at the site can also occasionally happen and lead to erythema and/or swelling. Other very uncommon findings experienced by patients may be stomach discomfort, nausea, or headaches, although the vast majority of patients do not feel anything at all. Anxiety and claustrophobia can be encountered in some patients and may require anxiolytics or sedatives in order to proceed with the PET scan.

One should pay great attention to the timing of the sedation in relation to the timing of the radiotracer injection in order not to affect the radiopharmaceutical biodistribution. This would then lead to inconclusive or erroneous interpretations.

Clinical Significance

A variety of clinical conditions benefit from neurological assessments with a PET scan. We will summarize them into the following categories:

Neurodegenerative Disorders

Dementias are considered a significant cause of morbidity in geriatric patients and significantly impact medical and socioeconomic outcomes. [13] Clinical diagnosis can be challenging and PET scans may play a role in providing an accurate and early diagnosis. [14][15] They are also predictive of disease progression and severity and can impact management. [16] A negative amyloid PET scan excludes the possibility of Alzheimer's type dementia. Patients with mild cognitive impairment (MCI) can be classified into their likelihood of developing dementia. [16][17] This is accomplished by using a combination of FDG, amyloid, and or tau PET scans. [18] This also allows earlier access to treatment to potentially slow disease progression and permits proper clinical decision-making. [16][17] 

Disease-modifying therapies are currently in clinical trials. FDG PET shows early on in AD a pattern of decreased glucose metabolism in the precuneus, posterior cingulate, and temporoparietal regions translating to underlying neuronal dysfunction. [14][15][16][17] As disease progresses, the frontal lobes are also affected. One should note that an amyloid PET scan will also be positive about 10 years before the clinical onset of AD. [19] Tau PET will show increased radiotracer deposition in the temporoparietal regions and the posterior cingulate. [20][21][22][23]

On the other hand, frontotemporal dementias will show a pattern of decreased FDG uptake in the anterior cerebral hemisphere and frontotemporal lobes. [24][20][25] The amyloid PET scan will generally be negative. [19]

In a large multicenter study, the original IDEAS (Imaging Dementia - Evidence for Amyloid Screening) study enrolled 11050 patients and showed that the use of amyloid scans changed management in 60.2% of MCI and 63.5% of dementia patients. Medication use was the most affected by the change. Amyloid scans changed the diagnosis in 35.6% of patients. [26]

Movements Disorders

Clinicians are frequently faced with patients presenting with parkinsonian-like syndromes. These patients have symptoms similar to Parkinson disease (PD) patients; however, they may not have the disease. Management of the different parkinsonian syndromes are different as well. FDOPA PET scans will be positive in parkinsonian syndromes. Decreased radiotracer uptake will be seen in the basal ganglia in patients with PD, corticobasal degeneration, multiple system atrophy, and progressive supranuclear palsy. However, patients with non-parkinsonian syndromes such as essential tremors, myoclonus, or other dystonia will have preserved FDOPA uptake. [27][28][29][30]

Neurooncological Disorders

FDG PET is no longer routinely used in assessing brain tumors and is on occasion used to evaluate brain tumor recurrence versus post-radiation necrosis changes when MRI results are equivocal. On the other hand, amino acid PET has taken a larger role in the clinical management of neurooncology patients. FDOPA can be used clinically in a variety of scenarios: [31][32]

• Differentiation of grade III and IV tumors from non-neoplastic lesions or grade I and II gliomas
• Prognostication of gliomas
• Guidance of an optimal biopsy site (e.g., site of maximum tracer uptake)
• Delineation of tumor extent for surgery and radiotherapy planning
• Differentiation of glioma recurrence from treatment-induced changes, e.g., pseudoprogression, radionecrosis
• Detection of malignant transformation in grade I and II gliomas
• Response assessment during and after radiotherapy and/or chemotherapy
• Differentiation of tumor response from pseudo-response during antiangiogenic therapy
• Intraoperative navigation

However, FDG PET still offers high clinical accuracy in primary brain lymphoma and is of great value in the initial diagnosis, follow-up, and treatment response assessments. [33][34]

Epilepsy 

FDG PET plays a major role in the presurgical workup of medically refractory epilepsy patients. One-third of epilepsy patients are medically refractory, and their seizures are not controlled with antiepileptic drugs. FDG PET will show decreased glucose metabolism in the seizure onset zone (SOZ) and sometimes along the epilepsy network. It allows accurate localization or at least lateralization of the SOZ that needs to be resected for seizure freedom or improved seizure control. [34][35][36][37] FDG PET offers prognostic information in the presurgical workup of medically refractory epilepsy patients.

Encephalitis

In encephalitis, FDG PET is the most sensitive imaging technique available. [38][9] A variety of patterns have been described depending on the timing of PET imaging in relation to the acute, subacute, or chronic phase of encephalitis. Acutely, increased glucose metabolism can be seen in the limbic system and the site of encephalitis in the cortex. Visual cortex and frontal lobe hypermetabolism or hypometabolism have also been described in specific pathologies. [35][39][40][41][42][43] Later on, these areas of hypermetabolism will start to exhibit decreased glucose metabolism during the chronic phase or following remission. [44][9]

Enhancing Healthcare Team Outcomes

Brain PET scans are advanced imaging techniques that require specialized expertise. Increased awareness of the clinical availability of these tools will enhance patient care. Proper utilization through integrated discussion between imaging experts and expert neurologists, epileptologists, neurosurgeons, movement disorder specialists, and neurooncologists will allow for improved diagnosis and improved patient outcomes. Multidisciplinary meetings can serve as a platform to enhance the appropriate and most effective use of these techniques.