[(18)F]Flutemetamol PET imaging and cortical biopsy histopathology for fibrillar amyloid ß detection in living subjects with normal pressure hydrocephalus: pooled analysis of four studies.

Molecular imaging techniques developed to 'visualize' amyloid in vivo represent a major achievement in Alzheimer's disease (AD) research. This pooled analysis of four studies determined the level of association between uptake of the fibrillar amyloid ß positron emission tomography (PET) imaging agent [(18)F]flutemetamol (Pittsburgh Compound B analog with a 5.5 times longer half-life to enable it to be used in the clinical setting) and neuritic plaques and fibrillar amyloid ß measured by pathologic staining of cortical region biopsy samples. Fifty-two patients with suspected normal pressure hydrocephalus underwent prospective (n = 30) or retrospective (n = 22) [(18)F]flutemetamol PET imaging for detection of cerebral cortical fibrillar amyloid ß and cortical brain biopsy during intracranial pressure measurement or ventriculo-peritoneal shunting. [(18)F]Flutemetamol uptake was quantified using standardized uptake value ratio (SUVR) with cerebellar cortex as the reference region. Tissue fibrillar amyloid ß was evaluated using immunohistochemical monoclonal antibody 4G8 and histochemical agents Thioflavin S and Bielschowsky silver stain, and an overall pathology result based on all available immunohistochemical and histochemical results. Biopsy site and contralateral [(18)F]flutemetamol SUVRs were significantly associated with neuritic plaque burden assessed with Bielschowsky silver stain (r (spearman's) = 0.61, p = 0.0001 for both), as was the composite SUVR with biopsy pathology (r (spearman's) = 0.74, p < 0.0001). SUVR and immunohistochemical results with 4G8 for detecting fibrillar amyloid ß were similar. Blinded image evaluation showed strong agreement between readers (κ = 0.86). Overall sensitivity and specificity by majority read were 93 and 100 %. Noninvasive in vivo [(18)F]flutemetamol PET imaging demonstrates strong concordance with histopathology for brain fibrillar amyloid ß, supporting its promise as a tool to assist physicians with earlier detection of the disease process and making diagnostic decisions about concomitant AD and other diseases associated with brain amyloidosis.

Correcting Diagnostic Test Sensitivity and Specificity for Patient Misclassifications Resulting from Use of an Imperfect Reference Standard.

Investigational diagnostic tests are validated by using a reference standard (RS). If the RS is imperfect (i.e., it has sensitivity [Se] and/or specificity [Sp] < 1), incorrect values for the investigational test's Se and Sp may result because of patient misclassification by the RS. Formulas were derived to correct a test's Se and Sp that were determined by using an imperfect RS. The following derived formulas correct for misclassification and give the true numbers of disease-positive [nDP] and disease-negative patients [nDN] from the apparent number of disease-positive and disease-negative patients (anDP and anDN), and the Se and Sp of the RS (SeR, SpR): nDP = (anDP × SpR + anDN × SpR − anDN)/JR; nDN = (anDP × SeR + anDN × SeR − anDP)/JR, where JR is Youden's Index for the RS (JR = SeR + SpR − 1). The following derived formulas give the correct Se and Sp of an investigational test (SeI and SpI): SeI = (anTPI × SpR − nDP × SeR × SpR + nDP × JR + nDN × SpR2 − nDN × SpR − SpR × anTNI + anTNI)/(nDP × JR); SpI = (anTPI − anTPI × SeR + nDP × SeR2 − nDP × SeR − SeR × nDN × SpR + nDN × JR + SeR × anTNI)/(nDN × JR), where anTPI is the apparent number of true-positive test results, and anTNI is the apparent number of true-negative test results. The derived formulas correct for patient misclassification by an imperfect RS and give the correct values of a diagnostic test's Se and Sp.

Nephrotoxicity of iodixanol versus ioversol in patients with chronic kidney disease: the Visipaque Angiography/Interventions with Laboratory Outcomes in Renal Insufficiency (VALOR) Trial.

BACKGROUND: Iso-osmolar contrast medium iodixanol has been reported to be less nephrotoxic than selected low-osmolar contrast media (LOCM) in chronic kidney disease (CKD) patients with diabetes mellitus. This study compared the nephrotoxicity of iodixanol and the LOCM ioversol in CKD patients undergoing coronary angiography. METHODS: This is a prospective double-blind trial in 337 patients with stable CKD who were randomly assigned to receive the iso-osmolar contrast medium iodixanol or the LOCM ioversol. The co-primary end points were the mean peak percentage change (MPPC) in baseline serum creatinine and the incidence of contrast-induced nephropathy (rise of > 0.5 mg/dL in baseline serum creatinine within 72 hours postcontrast) for the 2 contrast media in the 72-hour period after contrast administration. Prespecified analyses included stratification on diabetic state and the use of N-acetylcysteine. RESULTS: In the 299 patients with complete post-contrast media creatinine data, the incidence of contrast-induced nephropathy was 21.8% in the iodixanol subjects and 23.8% in the ioversol subjects (P = .78). For all patients, the MPPC was 14.7% with iodixanol and 20.0% with ioversol (P = .06), whereas in the subset of diabetic patients, this value was significantly lower in the iodixanol (12.9%) compared with the ioversol subjects (22.4%, P = .01). CONCLUSIONS: Overall, the nephrotoxicity associated with iodixanol was not significantly different from that observed with ioversol in CKD patients undergoing coronary angiography, although in diabetic patients, MPPC was significantly lower in the iodixanol group.

Use of Flutemetamol F 18-Labeled Positron Emission Tomography and Other Biomarkers to Assess Risk of Clinical Progression in Patients With Amnestic Mild Cognitive Impairment.

Importance: Patients with amnestic mild cognitive impairment (aMCI) may progress to clinical Alzheimer disease (AD), remain stable, or revert to normal. Earlier progression to AD among patients who were ß-amyloid positive vs those who were ß-amyloid negative has been previously observed. Current research now accepts that a combination of biomarkers could provide greater refinement in the assessment of risk for clinical progression. Objective: To evaluate the ability of flutemetamol F 18 and other biomarkers to assess the risk of progression from aMCI to probable AD. Design, Setting, and Participants: In this multicenter cohort study, from November 11, 2009, to January 16, 2014, patients with aMCI underwent positron emission tomography (PET) at baseline followed by local clinical assessments every 6 months for up to 3 years. Patients with aMCI (365 screened; 232 were eligible) were recruited from 28 clinical centers in Europe and the United States. Physicians remained strictly blinded to the results of PET, and the standard of truth was an independent clinical adjudication committee that confirmed or refuted local assessments. Flutemetamol F 18-labeled PET scans were read centrally as either negative or positive by 5 blinded readers with no knowledge of clinical status. Statistical analysis was conducted from February 19, 2014, to January 26, 2018. Interventions: Flutemetamol F 18-labeled PET at baseline followed by up to 6 clinical visits every 6 months, as well as magnetic resonance imaging and multiple cognitive measures. Main Outcomes and Measures: Time from PET to probable AD or last follow-up was plotted as a Kaplan-Meier survival curve; PET scan results, age, hippocampal volume, and aMCI stage were entered into Cox proportional hazards logistic regression analyses to identify variables associated with progression to probable AD. Results: Of 232 patients with aMCI (118 women and 114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive results detected on PET scan. By 36 months, the rates of progression to probable AD were 36.2% overall (81 of 224 patients), 53.6% (52 of 97) for patients with positive results detected on PET scan, and 22.8% (29 of 127) for patients with negative results detected on PET scan. Hazard ratios for association with progression were 2.51 (95% CI, 1.57-3.99; P < .001) for a positive ß-amyloid scan alone (primary outcome measure), 5.60 (95% CI, 3.14-9.98; P < .001) with additional low hippocampal volume, and 8.45 (95% CI, 4.40-16.24; P < .001) when poorer cognitive status was added to the model. Conclusions and Relevance: A combination of positive results of flutemetamol F 18-labeled PET, low hippocampal volume, and cognitive status corresponded with a high probability of risk of progression from aMCI to probable AD within 36 months.

Validation of an electronic image reader training programme for interpretation of [18F]flutemetamol ß-amyloid PET brain images.

OBJECTIVES: An electronic training programme (ETP) was developed for interpretation of images during routine clinical use of the PET amyloid imaging agent [F]flutemetamol injection (VIZAMYL). This study was carried out to validate the ETP. MATERIALS AND METHODS: Five nuclear medicine technologists (NMTs) and five readers previously inexperienced in amyloid image interpretation were required to self-train using the ETP and pass a test to participate. A total of 305 [F]flutemetamol PET images were then tested as the validation set, following preassessment and reorientation (where required) by one of five NMTs. Next, a new set of readers blinded to clinical information independently assessed all 305 images. Images had been acquired in previous studies from patients representing the full spectrum of cognitive capacity. When available, a standard of truth determined by histopathology or clinical history was used to derive sensitivity and specificity for image interpretation from this validation set. Randomly selected images (n=29) were read in duplicate to measure intrareader reproducibility. Images were read first without, and subsequently with anatomic images, if available. RESULTS: All NMTs and all readers scored 100% on the qualifying test. The interpretation of 135 cases without anatomic image support resulted in sensitivity ranging from 84% to 94% (majority 94%, median 92%) and specificity ranging from 77% to 96% (majority 92%, median 81%). Inter-reader agreement was very high, with most κ scores more than 0.8. Intrareader reproducibility ranged from 93 to 100%. CONCLUSION: The self-guided ETP effectively trained new amyloid PET image readers to accurately and reproducibly interpret [F]flutemetamol PET images.

Brain uptake and safety of Flutemetamol F 18 injection in Japanese subjects with probable Alzheimer's disease, subjects with amnestic mild cognitive impairment and healthy volunteers.

OBJECTIVE: This Phase 2 study assessed the performance of positron emission tomography (PET) brain images made with Flutemetamol F 18 Injection in detecting ß-amyloid neuritic plaques in Japanese subjects. METHODS: Seventy subjects (25 with probable Alzheimer's disease (pAD), 20 with amnestic mild cognitive impairment (aMCI), and 25 cognitively normal healthy volunteers[HVs]) underwent PET brain imaging after intravenous Flutemetamol F 18 Injection (185 MBq). Images were interpreted as normal or abnormal for neuritic plaque density by each of five non-Japanese and five Japanese readers who were blinded to clinical data. The primary efficacy analysis (based on HV and pAD data) was the agreement of the non-Japanese readers' image interpretations with the clinical diagnosis, resulting in estimates of positive percent agreement (PPA; based on AD subjects; similar to sensitivity) and negative percent agreement (NPA; based on HVs; similar to specificity). Secondary analyses included PPA and NPA for the Japanese readers; inter-reader agreement (IRA); intra-reader reproducibility (IRR); quantitative image interpretations (standardized uptake value ratios [SUVRs]) by diagnostic subgroup; test-retest variability in five pAD subjects; and safety. RESULTS: PPA was 92% for all non-Japanese readers and ranged from 88 to 92% for the Japanese readers. NPA ranged from 96 to 100% for both the non-Japanese readers and the Japanese readers. The majority image interpretations (the interpretations made independently by ≥3 of 5 readers) resulted in PPA values of 92 and 92% and NPA values of 100 and 96% for the non-Japanese and Japanese readers, respectively. IRA and IRR were strong. Composite SUVR values (mean of multiple regional values) allowed clear differentiation between pAD subjects and HVs. Test-retest variability ranged from 1.14 to 2.27%, and test-retest agreement of the blinded visual interpretations was 100% for all readers. Flutemetamol F 18 Injection was generally well tolerated. CONCLUSIONS: The detection of brain neuritic plaques in Japanese subjects using [18F]Flutemetamol PET images gave results highly consistent with clinical diagnosis, with non-Japanese and Japanese readers giving similar results. Inter-reader agreement and intra-reader reproducibility were high for both sets of readers. Visual delineation of abnormal and normal scans was corroborated by quantitative assessment, with low test-retest variability. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT02813070.

Performance of [18F]flutemetamol amyloid imaging against the neuritic plaque component of CERAD and the current (2012) NIA-AA recommendations for the neuropathologic diagnosis of Alzheimer's disease.

INTRODUCTION: Performance of the amyloid tracer [18F]flutemetamol was evaluated against three pathology standard of truth (SoT) measures including neuritic plaques (CERAD "original" and "modified" and the amyloid component of the 2012 NIA-AA guidelines). METHODS: After [18F]flutemetamol imaging, 106 end-of-life patients who died underwent postmortem brain examination for amyloid plaque load. Blinded positron emission tomography scan interpretations by five independent electronically trained readers were compared with pathology measures. RESULTS: By SoT, sensitivity and specificity of majority image interpretations were, respectively, 91.9% and 87.5% with "original CERAD," 90.8% and 90.0% with "modified CERAD," and 85.7% and 100% with the 2012 NIA-AA criteria. DISCUSSION: The high accuracy of either CERAD criteria suggests that [18F]flutemetamol predominantly reflects neuritic amyloid plaque density. However, the use of CERAD criteria as the SoT can result in some false-positive results because of the presence of diffuse plaques, which are accounted for when the positron emission tomography read is compared with the 2012 NIA-AA criteria.

Contrast dose-to-creatinine clearance ratio as a potential indicator of risk for radiocontrast-induced nephropathy: correlation of D/CrCL with area under the contrast concentration-time curve using iodixanol.

OBJECTIVES: Identification of risk factors is important for preventing radiocontrast-induced nephropathy (RCIN). Contrast dose and renal function have been shown in most but not all studies to be risk factors for RCIN. We are investigating the ratio of contrast dose to creatinine clearance (D/CrCL) as a risk indicator. Theory shows that the D/CrCL ratio equals the area under the concentration-time curve (AUC), an accepted measure of systemic exposure. This study investigated the correlation between calculated D/CrCL and experimentally measured AUC for the contrast agent iodixanol. MATERIALS AND METHODS: Experimental data on AUC from a phase 1 study of iodixanol were plotted against the D/CrCL ratio and the degree of correlation was determined. RESULTS: Experimentally determined AUC data correlate highly with the D/CrCL ratio. CONCLUSIONS: The D/CrCL ratio is a rapid and accurate way to estimate AUC for an iodinated x-ray contrast agent without the need for multiple blood samples.

Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density.

IMPORTANCE: In vivo imaging of brain ß-amyloid, a hallmark of Alzheimer disease, may assist in the clinical assessment of suspected Alzheimer disease. OBJECTIVE: To determine the sensitivity and specificity of positron emission tomography imaging with flutemetamol injection labeled with radioactive fluorine 18 to detect ß-amyloid in the brain using neuropathologically determined neuritic plaque levels as the standard of truth. DESIGN, SETTING, AND PARTICIPANTS: Open-label multicenter imaging study that took place at dementia clinics, memory centers, and hospice centers in the United States and England from June 22, 2010, to November 23, 2011. Participants included terminally ill patients who were 55 years or older with a life expectancy of less than 1 year. INTERVENTIONS: Flutemetamol injection labeled with radioactive fluorine 18 (Vizamyl; GE Healthcare) administration followed by positron emission tomography imaging and subsequent brain donation. MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of flutemetamol injection labeled with radioactive fluorine 18 positron emission tomography imaging for brain ß-amyloid. Images were reviewed without and with computed tomography scans and classified as positive or negative for ß-amyloid by 5 readers who were blind to patient information. In patients who died, neuropathologically determined neuritic plaque levels were used to confirm scan interpretations and determine sensitivity and specificity. RESULTS: Of 176 patients with evaluable images, 68 patients (38%) died during the study, were autopsied, and had neuritic plaque levels determined; 25 brains (37%) were ß-amyloid negative; and 43 brains (63%) were ß-amyloid positive. Imaging was performed a mean of 3.5 months (range, 0 to 13 months) before death. Sensitivity without computed tomography was 81% to 93% (median, 88%). Median specificity was 88%, with 4 of 5 of the readers having specificity greater than 80%. When scans were interpreted with computed tomography images, sensitivity and specificity improved for most readers but the differences were not significant. The area under the receiver operating curve was 0.90. There were no clinically meaningful findings in safety parameters. CONCLUSIONS AND RELEVANCE: This study showed that flutemetamol injection labeled with radioactive fluorine 18 was safe and had high sensitivity and specificity in an end-of-life population. In vivo detection of brain ß-amyloid plaque density may increase diagnostic accuracy in cognitively impaired patients.

Is ioflupane I123 injection diagnostically effective in patients with movement disorders and dementia? Pooled analysis of four clinical trials.

OBJECTIVES: To pool clinical trials of similar design to assess overall sensitivity and specificity of ioflupane I123 injection (DaTSCAN or ioflupane ((123)I)) to detect or exclude a striatal dopaminergic deficit disorder (SDDD), such as parkinsonian syndrome and dementia with Lewy bodies. DESIGN: Pooled analysis of three phase 3 and one phase 4 clinical trials. These four trials were selected because they were the four studies used for the US new drug application to the Food and Drug Administration (FDA). SETTING: Multicentre, open-label, non-randomised. PARTICIPANTS: Patients with either a movement disorder or dementia, and healthy volunteers. INTERVENTIONS: Ioflupane ((123)I) was administered. OUTCOME MEASURES: Images were assessed by panels of 3-5 blinded experts and/or on-site nuclear medicine physicians, classified as normal or abnormal and compared with clinical diagnosis (reference standard) to determine sensitivity and specificity. RESULTS: Pooling the four studies, 928 participants were enrolled, 849 were dosed and 764 completed their study. Across all studies, when images were assessed by on-site readers, ioflupane ((123)I) diagnostic effectiveness had an overall (95% CI) sensitivity of 91.9% (88.7% to 94.5%) and specificity of 83.6% (78.7% to 87.9%). When reads were conducted blindly by a panel of independent experts, the overall sensitivity was 88.7% (86.8% to 90.4%) and specificity was 91.2% (89.0% to 93.0%). CONCLUSIONS: In this pooled analysis, the visual assessment of ioflupane ((123)I) images provided high levels of sensitivity and specificity in detecting the presence/absence of an SDDD. Ioflupane ((123)I) imaging has the potential to improve diagnostic accuracy in patients with signs and symptoms of a movement disorder and/or dementia. TRIAL REGISTRATION NUMBER: NCT00209456.

Diagnostic effectiveness of quantitative [¹8F]flutemetamol PET imaging for detection of fibrillar amyloid ß using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus.

INTRODUCTION: PET imaging of amyloid-ß (Aß) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Aß pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Aß pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Aß (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies. RESULTS: Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result. CONCLUSION: Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results.