Clinicopathological Correlation: Dopamine and Amyloid PET Imaging with Neuropathology in Three Subjects Clinically Diagnosed with Alzheimer's Disease or Dementia with Lewy Bodies.

BACKGROUND: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid™) is selective for the neuritic plaque amyloid of Alzheimer's disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker. OBJECTIVE: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). METHODS: Three subjects who had PET imaging with both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared. RESULTS: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD. CONCLUSION: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed.

Relationship Between Clinicopathological Characteristics and PET/CT Uptake in Esophageal Squamous Cell Carcinoma: [18F]Alfatide versus [18F]FDG.

PURPOSE: To assess a novel radiotracer aluminum [18F]fluoride-1,4,7-triazacyclononane-triacetic acid-pegylated dimeric RGD ([18F]ALF-NOTA-PRGD2, denoted as [18F]Alfatide) for positron emission tomography (PET)/X-ray computed tomography (CT) and explore the relationships between clinicopathological characteristics and maximum standard uptake values in primary (SUVP) and metastatic lymph nodes (SUVLN) of patients with esophageal squamous cell carcinoma (ESCC), as verified by pathologic examination and compared with those obtained with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]DG) PET. PROCEDURES: We prospectively enrolled patients with newly diagnosed ESCC who agreed to undergo [18F]Alfatide PET/CT or [18F]FDG PET/CT scans before surgery at Shandong Cancer Hospital from May 2011 to July 2017. SUVs and the pathological tumor-node-metastasis (pTNM) stages of primary tumors and metastatic lymph nodes (LNs) were measured and confirmed pathologically. Immunohistochemical (IHC) staining for integrin αvß3 was performed on tumor samples (both primary tumors and metastatic LNs) collected from nine patients. RESULTS: Of 61 patients who underwent PET/CT scans, 46 then underwent curative surgery and were included in our analysis (n = 21 for [18F]Alfatide PET/CT and n = 25 for [18F]FDG PET/CT). No significant differences in the SUVP on [18F]Alfatide PET/CT or [18F]FDG PET/CT were observed among the cohorts according to gender, pathological stage, T stage, status of LNs, and differentiation (all P > 0.05). The SUVLN differed significantly between the pathological stages and status of LNs both on [18F]Alfatide PET/CT (P = 0.03, 0.003) and [18F]FDG PET/CT (P = 0.001. < 0.001), but not according to gender (P = 0.128, 0.129), T stage (P = 0.791, 0.727), or tumor differentiation (P = 0.049, 0.053). Significant positive correlations were observed between the SUVLN on [18F]Alfatide PET/CT and [18F]FDG PET/CT, and pathological stage (r = 0.52, P = 0.016; r = 0.503, P = 0.01), LN status (r = 0.73, P < 0.001; r = 0.649, P < 0.001), and differentiation (r = 0.509, P < 0.019; r = 0.459, P = 0.021) were observed. No significant differences were found between the relationships of SUVP with SUVLN, length, age, gender, pathological stage, T stage, status of LN, or differentiation, or of SUVLN with length, age, gender, or T stage both on [18F]Alfatide PET/CT and [18F]FDG PET/CT (all P > 0.05). The quantitated expression levels of αvß3 in primary tumors and metastatic LNs were 1.67 ± 1.12 and 3.42 ± 2.93, respectively (P = 0.031). CONCLUSIONS: Our results suggest that SUVLN is influenced by pathological stage, LN status, and differentiation. SUVLN may therefore serve as a new parameter for risk stratification of with ESCC patients. Moreover, [18F]Alfatide PET can provide complementary molecular information about ESCC metastasis.

An exploratory efficacy study of the amyloid imaging agent [(18)F]flutemetamol in Japanese Subjects.

AIM: The aim of the study presented was to investigate the brain uptake properties of the amyloid PET agent [(18)F]flutemetamol in Japanese healthy controls and clinically probable Alzheimer's disease (AD) patients, and to make a comparison with the results of a previously performed study on Caucasian subjects. [(18)F]flutemetamol was recently approved by the American Food and Drug Administration and the European Medicines Agency for visualization of amyloid in vivo. Since the first clinical study of [(18)F]flutemetamol-an (18)F derivative of the PET tracer 11C-Pittsburgh Compound B targeting ß-amyloid--took place, several clinical studies have been performed, but few focusing on a Japanese population. METHODS: In the Step A, three elderly healthy volunteers and three AD subjects underwent dynamic PET scanning 0-30 and 60-150 min after injection of 185 MBq [(18)F]flutemetamol. The brain volume of distribution (VT) was quantified using Logan's linear graphical analysis and as standardized uptake value ratios (SUVR) with a cerebellar reference. The optimal acquisition window was determined from brain time activity curves for Step B. In the Step B, 5 AD and 5 elderly healthy volunteers were scanned from 80 to 140 min after intravenous injection of [(18)F]flutemetamol. The data from the two parts were pooled for estimation of overall efficacy. RESULTS: [(18)F]Flutemetamol injection was shown to be safe-no serious adverse events were reported during this study. A simplified SUVR estimate of the uptake of [(18)F]flutemetamol using a time window of 85-115 min post injection successfully discriminated AD cases from healthy volunteers. AD subjects showed an elevated tracer uptake in prefrontal cortex, the lateral temporal cortex and precuneus amongst other regions. No significant [(18)F]flutemetamol PET differences could be seen between the Japanese AD cases in this study and those from an earlier Caucasian study, or between control subjects in Japanese and Caucasian studies. CONCLUSIONS: This study supports the use of [(18)F]flutemetamol PET in Japanese population as a marker of the presence of fibrillar ß-amyloid. The lack of differences between the Japanese cohort and those from a previous Caucasian cohort supports the extrapolation of results from other Caucasian [(18)F]flutemetamol PET studies to the Japanese population.

Comparison of the biological effects of (18)F at different intracellular levels.

We herein examined the biological effects of cells treated with (18)F labeled drugs for positron emission tomography (PET). The relationship between the intracellular distribution of (18)F and levels of damaged DNA has yet to be clarified in detail. We used culture cells (Chinese Hamster Ovary cells) treated with two types of (18)F labeled drugs, fluorodeoxyglucose (FDG) and fluorine ion (HF). FDG efficiently accumulated in cells, whereas HF did not. To examine the induction of DNA double strand breaks (DSB), we measured the number of foci for 53BP1 that formed at the site of DNA DSB. The results revealed that although radioactivity levels were the same, the induction of 53BP1 foci was stronger in cells treated with (18)F-FDG than in those treated with (18)F-HF. The clonogenic survival of cells was significantly lower with (18)F-FDG than with (18)F-HF. We concluded that the efficient accumulation of (18)F in cells led to stronger biological effects due to more severe cellular lethality via the induction of DNA DSB.

PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer's disease and Lewy body disorders.

BACKGROUND: Biomarkers based on the underlying pathology of Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB) have the potential to improve diagnosis and understanding of the substrate for cognitive impairment in these disorders. The objective of this study was to compare the patterns of amyloid and dopamine PET imaging in patients with AD, DLB and Parkinson's disease (PD) using the amyloid imaging agent florbetapir F 18 and 18F-AV-133 (florbenazine), a marker for vesicular monamine type 2 transporters (VMAT2). METHODS: Patients with DLB and AD, Parkinson's disease (PD) and healthy controls (HC) were recruited for this study. On separate days, subjects received intravenous injections of florbetapir, and florbenazine. Amyloid burden and VMAT2 density were assessed quantitatively and by binary clinical interpretation. Imaging results for both tracers were compared across the four individual diagnostic groups and for combined groups based on underlying pathology (AD/DLB vs. PD/HC for amyloid burden and PD/DLB vs. AD/HC for VMAT binding) and correlated with measures of cognition and parkinsonism. RESULTS: 11 DLB, 10 AD, 5 PD, and 5 controls participated in the study. Amyloid binding was significantly higher in the combined AD/DLB patient group (n = 21) compared to the PD/HC groups (n = 10, mean SUVr: 1.42 vs. 1.07; p = 0.0006). VMAT2 density was significantly lower in the PD/DLB group (n = 16) compared to the AD/ HC group (n = 15; 1.83 vs. 2.97; p < 0.0001). Within the DLB group, there was a significant correlation between cognitive performance and striatal florbenazine binding (r = 0.73; p = 0.011). CONCLUSIONS: The results of this study show significant differences in both florbetapir and florbenazine imaging that are consistent with expected pathology. In addition, VMAT density correlated significantly with cognitive impairment in DLB patients (ClinicalTrials.gov identifier: NCT00857506, registered March 5, 2009).

Florbetapir (18F) for brain amyloid positron emission tomography: highlights on the European marketing approval.

Florbetapir (18F) for brain amyloid positron emission tomography (PET) imaging has been recently approved in Europe to estimate ß-amyloid neuritic plaque density in the brain when the subject is still alive. Such density is one of the key issues for the definitive diagnosis of Alzheimer's disease (AD) at autopsy. This capability of florbetapir (18F) is regarded as a significant improvement in the diagnostic procedures for adult patients with cognitive impairment who are being evaluated for AD and other causes of cognitive impairment. The current paper highlights the specific characteristics of the European marketing authorization of florbetapir (18F).

(-)-[(18) F]Flubatine: evaluation in rhesus monkeys and a report of the first fully automated radiosynthesis validated for clinical use.

(-)-[(18) F]Flubatine was selected for clinical imaging of α4 ß2 nicotinic acetylcholine receptors because of its high affinity and appropriate kinetic profile. A fully automated synthesis of (-)-[(18) F]flubatine as a sterile isotonic solution suitable for clinical use is reported, as well as the first evaluation in nonhuman primates (rhesus macaques). (-)-[(18) F]Flubatine was prepared by fluorination of the Boc-protected trimethylammonium iodide precursor with [(18) F]fluoride in an automated synthesis module. Subsequent deprotection of the Boc group with 1-M HCl yielded (-)-[(18) F]flubatine, which was purified by semi-preparative HPLC. (-)-[(18) F]Flubatine was prepared in 25% radiochemical yield (formulated for clinical use at end of synthesis, n = 3), >95% radiochemical purity, and specific activity = 4647 Ci/mmol (171.9 GBq/µmol). Doses met all quality control criteria confirming their suitability for clinical use. Evaluation of (-)-[(18) F]flubatine in rhesus macaques was performed with a Concorde MicroPET P4 scanner (Concorde MicroSystems, Knoxville, TN). The brain was imaged for 90 min, and data were reconstructed using the 3-D maximum a posteriori algorithm. Image analysis revealed higher uptake and slower washout in the thalamus than those in other areas of the brain and peak uptake at 45 min. Injection of 2.5 µg/kg of nifene at 60 min initiated a slow washout of [(18) F]flubatine, with about 25% clearance from the thalamus by the end of imaging at 90 min.

Florbetapir (18F), a PET imaging agent that binds to amyloid plaques for the potential detection of Alzheimer's disease.

Florbetapir (18F), being developed by Avid Radiopharmaceuticals, is an 18F-labeled PET tracer binding to amyloid-ß (Aß) plaques for the potential detection of Alzheimer's disease (AD). Preclinical studies indicated high binding affinity of florbetapir (18F) to Aß fibrils and specific labeling of Aß plaques in the cortical regions and hippocampus. In phase I and II clinical trials, florbetapir (18F) clearly differentiated patients with AD from healthy controls and uptake was most prominent in the precuneus. The neocortical-to-cerebellar tracer uptake ratio reached a plateau within 50 min post-injection and high-quality images were acquired with 5 to 10 min image acquisition time with 370 MBq of florbetapir (18F). Results from an ongoing phase III clinical trial confirmed a strong correlation between florbetapir (18F) PET images and postmortem assessment of Aß deposition. No serious adverse events were reported in any of the clinical trials of florbetapir (18F). At the time of publication, a marketing application for florbetapir (18F) had been submitted to the US FDA. The fast kinetics and strong evidences of radiological-pathological correlation are advantages of florbetapir (18F) over other 18F-labeled amyloid PET tracers. This tracer has a potential to serve as an agent for preclinical detection of AD-related pathology in the large elderly population.

Measurement of the residual radioactivity induced in the front foil of a target assembly in a modern medical cyclotron.

The levels of residual radioactivity induced in Havar foils at the entrance of a high-pressure 18O-enriched water target used for the production of 18F- in a medical cyclotron with 16 MeV protons have been determined using high-resolution gamma-ray spectrometry. Whole body and skin dose rates arising from exposure to these foils during their periodic replacement have been estimated. The results indicate that irradiated foils do not represent a significant radiological hazard for the cyclotron operating staff and that no waste disposal difficulties should be encountered after an appropriate 'cooling' period of 2 years.

Practical aspects of radiation safety for using fluorine-18.

The use of positron-emitting nuclides is becoming routine in nuclear medicine departments today. Introducing these nuclides into the nuclear medicine department can be a smooth transition by instituting educational lectures, radiation safety protocols and patient education. The radiation safety concerns of the technical staff, physicians and ancillary personnel are important and must be addressed. Nuclear medicine departments can be optimistic about implementing PET imaging while staying well within ALARA guidelines. After reading this article, the technologist should be able to: (a) describe at least three ways to reduce the radiation dose to the technologist during the performance of PET imaging procedures with 18F; (b) discuss the relationships between gamma-ray energy, the amount of activity administered to a patient, exposure time and occupational dose; and (c) describe one strategy to minimize the radiation dose to the bladder in patients who have received 18F.