Rikard Owenius

18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial.

The most widely studied positron emission tomography ligand for in vivo β‐amyloid imaging is 11C‐Pittsburgh compound B (11C‐PIB). Its availability, however, is limited by the need for an on‐site cyclotron. Validation of the 18F‐labeled PIB derivative 18F‐flutemetamol could significantly enhance access to this novel technology.

Phase 1 Study of the Pittsburgh Compound B Derivative 18F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease

11C-Pittsburgh compound B (PiB) marks Aβ amyloidosis, a key pathogenetic process in Alzheimer disease (AD). The use of 11C-PiB is limited to centers with a cyclotron. Development of the 18F-labeled thioflavin derivative of PiB, 18F-flutemetamol, could hugely increase the availability of this new technology. The aims of this phase 1 study were to perform brain kinetic modeling of 18F-flutemetamol, optimize the image acquisition procedure, and compare methods of analysis (step 1) and to compare 18F-flutemetamol brain retention in AD patients versus healthy controls in a proof-of-concept study (steps 1 and 2). Methods: In step 1, 3 AD patients (Mini-Mental State Examination, 22–24) and 3 elderly healthy controls were scanned dynamically during windows of 0–90, 150–180, and 220–250 min after injection of approximately 180 MBq of 18F-flutemetamol, with arterial sampling. We compared different analysis methods (compartmental modeling, Logan graphical analysis, and standardized uptake value ratios) and determined the optimal acquisition window for step 2. In step 2, 5 AD patients (Mini-Mental State Examination, 20–26) and 5 elderly healthy controls were scanned from 80 to 170 min after injection. To determine overall efficacy, steps 1 and 2 were pooled and standardized uptake value ratios were calculated using cerebellar cortex as a reference region. Results: No adverse events were reported. There was a strong correlation between uptake values obtained with the different analysis methods. From 80 min after injection onward, the ratio of neocortical to cerebellar uptake was maximal and only marginally affected by scan start time or duration. AD patients showed significantly increased standardized uptake value ratios in neocortical association zones and striatum, compared with healthy controls, whereas uptake in white matter, cerebellum, and pons did not differ between groups. Two AD patients were 18F-flutemetamol–negative and 1 healthy control was 18F-flutemetamol–positive. Conclusion: 18F-flutemetamol uptake can be readily quantified. This phase 1 study warrants further studies to validate this 18F-labeled derivative of PiB as a biomarker for Aβ amyloidosis.

Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid β-Amyloid 42: A Cross-Validation Study Against Amyloid Positron Emission Tomography

IMPORTANCE Before adding cerebrospinal fluid (CSF) biomarkers to the diagnostic workup of Alzheimer disease, it needs to be determined whether CSF biomarkers analyzed in routine clinical practice can reliably predict cortical β-amyloid (Aβ) deposition. OBJECTIVES To study whether CSF biomarkers, analyzed consecutively in routine clinical practice during 2 years, can predict cortical Aβ deposition and to establish a threshold for Aβ42 abnormality. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study (The Swedish BioFINDER [Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably] Study) was conducted at 3 memory clinics. It involved consecutively referred, nondemented patients with mild cognitive symptoms (original cohort, n = 118; validation cohort, n = 38). EXPOSURES Amyloid positron emission tomography imaging with 18F-flutemetamol. MAIN OUTCOMES AND MEASURES Analyses of CSF Aβ42, total tau, and phosphorylated tau using an enzyme-linked immunosorbent assay (INNOTEST) in clinical samples. RESULTS The agreement between Aβ classification with CSF Aβ42 and 18F-flutemetamol positron emission tomography was very high (κ = 0.85). Of all the cases, 92% were classified identically using an Aβ42 cutoff of 647 pg/mL or less. Cerebrospinal fluid Aβ42 predicted abnormal cortical Aβ deposition accurately (odds ratio, 165; 95% CI, 39-693; area under the receiver operating characteristic curve, 0.94; 95% CI, 0.88-0.97). The association was independent of age, sex, APOE (apolipoprotein E) genotype, hippocampal volume, memory, and global cognition (adjusted odds ratio, 169; 95% CI, 25-1143). Using ratios of CSF Aβ42:tau or Aβ42:phosphorylated tau did not improve the prediction of Aβ deposition. Cerebrospinal fluid Aβ42 correlated significantly with Aβ deposition in all cortical regions. The highest correlations were in regions with high 18F-flutemetamol retention (eg, posterior cingulum and precuneus, r = -0.72). 18F-flutemetamol retention, but not CSF Aβ42, correlated significantly with global cognition (r = -0.32), memory function (r = -0.28), and hippocampal volume (r = -0.36) among those with abnormal Aβ deposition. Finally, the CSF Aβ42 cutoff derived from the original cohort (≤647 pg/mL) had an equally high agreement (95%; κ = 0.89) with 18F-flutemetamol positron emission tomography in the validation cohort. CONCLUSIONS AND RELEVANCE Cerebrospinal fluid Aβ42 analyzed consecutively in routine clinical practice at an accredited laboratory can be used with high accuracy to determine whether a patient has normal or increased cortical Aβ deposition and so can be valuable for the early diagnosis of Alzheimer disease. Abnormal 18F-flutemetamol retention levels correlate with disease stage in patients with mild cognitive symptoms, but this is not the case for CSF Aβ42 measurements.

Localized Prostate Cancer Detection with 18F FACBC PET/CT: Comparison with MR Imaging and Histopathologic Analysis

PURPOSE To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid ((18)F FACBC) in patients with localized prostate cancer, benign prostatic hyperplasia (BPH), and normal prostate tissue and to evaluate its potential utility in delineation of intraprostatic cancers in histopathologically confirmed localized prostate cancer in comparison with magnetic resonance (MR) imaging. MATERIALS AND METHODS Institutional review board approval and written informed consent were obtained for this HIPAA-compliant prospective study. Twenty-one men underwent dynamic and static abdominopelvic (18)F FACBC combined positron emission tomography (PET) and computed tomography (CT) and multiparametric (MP) 3-T endorectal MR imaging before robotic-assisted prostatectomy. PET/CT and MR images were coregistered by using pelvic bones as fiducial markers; this was followed by manual adjustments. Whole-mount histopathologic specimens were sliced with an MR-based patient-specific mold. (18)F FACBC PET standardized uptake values (SUVs) were compared with those at MR imaging and histopathologic analysis for lesion- and sector-based (20 sectors per patient) analysis. Positive and negative predictive values for each modality were estimated by using generalized estimating equations with logit link function and working independence correlation structure. RESULTS (18)F FACBC tumor uptake was rapid but reversible. It peaked 3.6 minutes after injection and reached a relative plateau at 15-20 minutes (SUVmax[15-20min]). Mean prostate tumor SUVmax(15-20min) was significantly higher than that of the normal prostate (4.5 ± 0.5 vs 2.7 ± 0.5) (P < .001); however, it was not significantly different from that of BPH (4.3 ± 0.6) (P = .27). Sector-based comparison with histopathologic analysis, including all tumors, revealed sensitivity and specificity of 67% and 66%, respectively, for (18)F FACBC PET/CT and 73% and 79%, respectively, for T2-weighted MR imaging. (18)F FACBC PET/CT and MP MR imaging were used to localize dominant tumors (sensitivity of 90% for both). Combined (18)F FACBC and MR imaging yielded positive predictive value of 82% for tumor localization, which was higher than that with either modality alone (P < .001). CONCLUSION (18)F FACBC PET/CT shows higher uptake in intraprostatic tumor foci than in normal prostate tissue; however, (18)F FACBC uptake in tumors is similar to that in BPH nodules. Thus, it is not specific for prostate cancer. Nevertheless, combined (18)F FACBC PET/CT and T2-weighted MR imaging enable more accurate localization of prostate cancer lesions than either modality alone.

Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease.

IMPORTANCE Several studies suggest that the apolipoprotein E (APOE) ε4 allele modulates cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42). Whether this effect is secondary to the association of the APOE ε4 allele with cortical Aβ deposition or whether APOE ε4 directly influences CSF levels of Aβ42 independently of Aβ pathology remains unknown. OBJECTIVE To evaluate whether the APOE genotype affects the diagnostic accuracy of CSF biomarkers for Alzheimer disease (AD), in particular Aβ42 levels, and whether the association of APOE ε4 with CSF biomarkers depends on cortical Aβ status. DESIGN, SETTING, AND PARTICIPANTS We collected data from 4 different centers in Sweden, Finland, and Germany. Cohort A consisted of 1345 individuals aged 23 to 99 years with baseline CSF samples, including 309 with AD, 287 with prodromal AD, 399 with stable mild cognitive impairment, 99 with dementias other than AD, and 251 controls. Cohort B included 105 nondemented younger individuals (aged 20-34 years) with CSF samples available. Cohort C included 118 patients aged 60 to 80 years with mild cognitive symptoms who underwent flutemetamol F 18 ([18F]flumetamol) positron emission tomography amyloid imaging and CSF tap. EXPOSURES Standard care. MAIN OUTCOMES AND MEASURES Cerebrospinal fluid levels of Aβ42 and total and phosphorylated tau in relation to the APOE ε2/ε3/ε4 polymorphism in different diagnostic groups and in cases with or without cortical uptake of [18F]flutemetamol. RESULTS The CSF levels of Aβ42 but not total and phosphorylated tau were lower in APOE ε4 carriers compared with noncarriers irrespective of diagnostic group (cohort A). Despite this, CSF levels of Aβ42 differed between participants with AD when compared with controls and those with stable mild cognitive impairment, even when stratifying for APOE genotype (P < .001 to P = .006). Multiple binary logistic regression revealed that CSF levels of Aβ42 and APOE ε4 genotype were independent predictors of AD diagnosis. In cohort B, APOE ε4 carrier status did not influence CSF levels of Aβ42. Moreover, when stratifying for cortical uptake of [18F]flutemetamol in cohort C, APOE ε4 genotype did not influence CSF levels of Aβ42. This result was replicated in a cohort with individuals from the Alzheimers Disease Neuroimaging Initiative (ADNI) using carbon 11-labeled Pittsburgh Compound B scanning. CONCLUSIONS AND RELEVANCE Cerebrospinal fluid levels of Aβ42 are strongly associated with the diagnosis of AD and cortical Aβ accumulation independent of APOE genotype. The clinical cutoff for CSF levels of Aβ42 should be the same for all APOE genotypes.

Anti-1-Amino-3-18F-Fluorocyclobutane-1-Carboxylic Acid: Physiologic Uptake Patterns, Incidental Findings, and Variants That May Simulate Disease

Anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid (18F-FACBC) is a synthetic amino acid analog PET radiotracer undergoing clinical trials for the evaluation of prostate and other cancers. We aimed to describe common physiologic uptake patterns, incidental findings, and variants in patients who had undergone 18F-FACBC PET. Methods: Sixteen clinical trials involving 611 18F-FACBC studies from 6 centers, which included dosimetry studies on 12 healthy volunteers, were reviewed. Qualitative observations of common physiologic patterns, incidental uptake, and variants that could simulate disease were recorded and compared with similar observations in studies of the healthy volunteers. Quantitative analysis of select data and review of prior published reports and observations were also made. Results: The liver and pancreas demonstrated the most intense uptake. Moderate salivary and pituitary uptake and variable mild to moderate bowel activity were commonly visualized. Moderate bone marrow and mild muscle activity were present on early images, with marrow activity decreasing and muscle activity increasing with time. Brain and lungs demonstrated activity less than blood pool. Though 18F-FACBC exhibited little renal excretion or bladder uptake during the clinically useful early imaging time window, mild to moderate activity might accumulate in the bladder and interfere with evaluation of adjacent prostate bed and seminal vesicles in 5%–10% of patients. Uptake might also occur from benign processes such as infection, inflammation, prostatic hyperplasia, and metabolically active benign bone lesions such as osteoid osteoma. Conclusion: Common physiologic uptake patterns were similar to those noted in healthy volunteers. The activity in organs followed the presence of amino acid transport and metabolism described with other amino acid–based PET radiotracers. As with other PET radiotracers such as 18F-FDG, focal nonphysiologic uptake may represent incidental malignancy. Uptake due to benign etiologies distinct from physiologic background also occurred and could lead to misinterpretations if the reader is unaware of them.

Gaussian Process Models of Dynamic PET for Functional Volume Definition in Radiation Oncology

In routine oncologic positron emission tomography (PET), dynamic information is discarded by time-averaging the signal to produce static images of the “standardised uptake value” (SUV). Defining functional volumes of interest (VOIs) in terms of SUV is flawed, as values are affected by confounding factors and the chosen time window, and SUV images are not sensitive to functional heterogeneity of pathological tissues. Also, SUV iso-contours are highly affected by the choice of threshold and no threshold, or other SUV-based segmentation method, is universally accepted for a given VOI type. Gaussian Process (GP) time series models describe macro-scale dynamic behavior arising from countless interacting micro-scale processes, as is the case for PET signals from heterogeneous tissue. We use GPs to model time-activity curves (TACs) from dynamic PET and to define functional volumes for PET oncology. Probabilistic methods of tissue discrimination are presented along with novel contouring methods for functional VOI segmentation. We demonstrate the value of GP models for voxel classification and VOI contouring of diseased and metastatic tissues with functional heterogeneity in prostate PET. Classification experiments reveal superior sensitivity and specificity over SUV calculation and a TAC-based method proposed in recent literature. Contouring experiments reveal differences in shape between gold-standard and GP VOIs and correlation with kinetic models shows that the novel VOIs contain extra clinically relevant information compared to SUVs alone. We conclude that the proposed models offer a principled data analysis technique that improves on SUVs for oncologic VOI definition. Continuing research will generalize GP models for different oncology tracers and imaging protocols with the ultimate goal of clinical use including treatment planning.

Pons as an alternative reference region in [18F]flutemetamol quantification of amyloidosis

Background: Quantitative PET-imaging of amyloidosis can be performed using [C]PiB and analysis of volume of interest based SUV ratios. Cerebellum is generally used as reference region in this simplified analysis to avoid invasive blood sampling. An [F] tracer for imaging of amyloidosis would increase the availability compared to [C] compounds and enable the use of PET in the clinical diagnosis of Alzheimers disease (AD), as it has a half life of 110 min. In this abstract, data from the previously reported Phase II study of [F]flutemetamol—a [F] derivative of PiB—is used to compare cerebellum and pons as reference regions, with the incitement that pons might be a more appropriate reference region as it is easier to delineate correctly and not in risk of being positioned outside the PET scanners field-of-view.

Subject classification from [18F]flutemetamol data into categories of raised or low levels of beta-amyloid: Concordance between quantitative and visual assessment

GE Healthcare, Uppsala, Sweden GE Healthcare, Amersham, UK KU Leuven, Leuven, Belgium CRC/University of Liege, Liege, Belgium Rigshospitalet, Copenhagen, Denmark Imperial College London, London, UK GE Healthcare, Amersham, UK Purpose: The PET ligand [F]flutemetamol is structurally identical to [C]PiB, apart from the radioisotope, and is being developed as a biomarker for detection of fibrillar β amyloid (Aβ) aggregates, one of the pathological hallmarks of Alzheimers disease (AD). The objective of this study was to examine how well the regional cerebral-to-cerebellum standardized uptake value ratio (SUVR) from a [F]flutemetamol PET scan allowed to separate subjects with probable AD from healthy volunteers (HV), as well as to assign patients with mild cognitive impairment (MCI) to categories of either raised or low levels of Aβ. In addition, this quantitative classification was compared with the categorization achieved by means of visual assessment.