Gregory Klein

The influence of biological and technical factors on quantitative analysis of amyloid PET: Points to consider and recommendations for controlling variability in longitudinal data

In vivo imaging of amyloid burden with positron emission tomography (PET) provides a means for studying the pathophysiology of Alzheimers and related diseases. Measurement of subtle changes in amyloid burden requires quantitative analysis of image data. Reliable quantitative analysis of amyloid PET scans acquired at multiple sites and over time requires rigorous standardization of acquisition protocols, subject management, tracer administration, image quality control, and image processing and analysis methods. We review critical points in the acquisition and analysis of amyloid PET, identify ways in which technical factors can contribute to measurement variability, and suggest methods for mitigating these sources of noise. Improved quantitative accuracy could reduce the sample size necessary to detect intervention effects when amyloid PET is used as a treatment end point and allow more reliable interpretation of change in amyloid burden and its relationship to clinical course.

Method to correlate 1H MRSI and 18FDG-PET

The in vivo neuronal contribution to human cerebral metabolic rate of glucose (CMRglc), measured by 18FDG‐PET, is unknown. Examining the effect of 1H MRSI‐derived N‐acetyl aspartate (NAA) concentration on positron emission tomography (PET) measures of metabolic activity might indicate the relationship of CMRglc to neuron density. In a population of 19 demented, cognitively impaired, and control subjects, the Müller‐Gärtner algorithm was applied to whole‐brain PET data to isolate the PET signal originating in cortical gray matter alone (GMPET). An analogous procedure applied to multislice proton MRSI data yielded the N‐acetyl aspartate concentration in cortical gray matter (GMNAA). In 18 of 19 subjects, a significant linear regression (P < 0.05) resulted when GMPET was plotted against GMNAA, whereby GMPET was higher for higher GMNAA. Thissuggests that CMRglc rises linearly with increasing neuron density in gray matter. This method may be used to investigate the relationship of CMRglc to neurons in various conditions. Magn Reson Med 43:244–250, 2000.

Amyloid PET Screening for Enrichment of Early-Stage Alzheimer Disease Clinical Trials: Experience in a Phase 1b Clinical Trial.

Amyloid positron emission tomography (PET) imaging is being investigated as a screening tool to identify amyloid-positive patients as an enrichment strategy for Alzheimer disease (AD) clinical trial enrollment. In a multicenter, phase 1b trial, patients meeting clinical criteria for prodromal or mild AD underwent florbetapir PET scanning at screening. PET, magnetic resonance imaging, and coregistered PET/magnetic resonance imaging scans were reviewed by 2 independent readers and binary visual readings tabulated. Semiquantitative values of cortical to whole cerebellar standard uptake value ratios were computed (threshold 1.10). Of 278 patients with an evaluable PET scan, 170 (61%) and 185 (67%) were amyloid-positive by visual reading and quantitative analysis, respectively; 39% were excluded from the study due to an amyloid-negative scan based on visual readings. More ApoE &egr;4 carriers than noncarriers were amyloid-positive (80% vs. 43%). Comparison of visual readings with quantitative results identified 21 discordant cases (92% agreement). Interreader and intrareader agreements from visual readings were 98% and 100%, respectively. Amyloid PET imaging is an effective and feasible screening tool for enrollment of amyloid-positive patients with early stages of AD into clinical trials.

24-MONTH AMYLOID PET RESULTS OF THE GANTENERUMAB HIGH-DOSE OPEN LABEL EXTENSION STUDIES

doses of LY3002813 resulted in significant reductions in florbetapir F18 tracer uptake on PET by 3 months, with further reduction with repeat dosing over time. For the initial dosing cohorts, reductions in florbetapir F18 at 3 months were -11.8 (SD 21.1) centiloids after a single dose of 10 mg/kg IV (n1⁄47); -39.0 (SD 18.1) centiloids after a single dose of 20mg/kg IV (n1⁄47); and -44.5 (SD 24.3) centiloids for 10mg/kg IVadministered every two weeks (n1⁄410). In patients with up to 72 weeks of follow-up after completion of treatment, the reduced post-treatment florbetapir F18 PET SUVr levels were maintained, without returning to pre-dose baseline levels. Conclusions: LY3002813 demonstrates significant, rapid and sustained reduction in cortical amyloid plaque in Alzheimer’s patients.

UPDATE ON THE SAFETY AND TOLERABILITY OF GANTENERUMAB IN THE ONGOING OPEN-LABEL EXTENSION (OLE) OF THE MARGUERITE ROAD STUDY IN PATIENTS WITH MILD ALZHEIMER’S DISEASE (AD) AFTER APPROXIMATELY TWO YEARS OF STUDY DURATION

dosing, patients were analyzed in three groups: the MRDB placebo cohort (MR-Pbo), theMRDB cohort pretreated with gantenerumab (MR-Gant) and a SR DB cohort combining patients originally assigned to placebo or gantenerumab (SR). Change from baseline OLE in amyloid burden was assessed via global and regional standard uptake value ratio (SUVR) analysis of florbetapir PET at months 12 and 24. Results: Preliminary analysis of 40 patients (MR-Pbo, 14; MR-Gant, 17; SR, 9) showed mean (SD) 12-month changes in absolute SUVR units of -0.24 (0.21), -0.27 (0.14), and -0.13 (0.16) in the MR-Pbo, MR-Gant, and SR groups, respectively. Reductions in amyloid burden and percent of patients below the amyloid positivity threshold using an updated data cut (May 30, 2018) will be reported. Approximately 37 patients (MR-Pbo 12; MR-Gant 12; SR 13) will have their OLE 24 month PET scan for this analysis, not accounting for patient drop-out. Conclusions:Updated findings are expected to confirm preliminary results and show continued reduction in amyloid burden with ongoing treatment up to 24 months. This work supports our planned Phase 3 program using high doses of gantenerumab. 1. Klein, CTAD 2017.

UPDATE ON THE SAFETY AND TOLERABILITY OF GANTENERUMAB IN THE ONGOING OPEN-LABEL EXTENSION OF THE SCARLET ROAD STUDY IN PATIENTS WITH PRODROMAL ALZHEIMER'S DISEASE AFTER APPROXIMATELY 2 YEARS OF STUDY DURATION

dosing, patients were analyzed in three groups: the MRDB placebo cohort (MR-Pbo), theMRDB cohort pretreated with gantenerumab (MR-Gant) and a SR DB cohort combining patients originally assigned to placebo or gantenerumab (SR). Change from baseline OLE in amyloid burden was assessed via global and regional standard uptake value ratio (SUVR) analysis of florbetapir PET at months 12 and 24. Results: Preliminary analysis of 40 patients (MR-Pbo, 14; MR-Gant, 17; SR, 9) showed mean (SD) 12-month changes in absolute SUVR units of -0.24 (0.21), -0.27 (0.14), and -0.13 (0.16) in the MR-Pbo, MR-Gant, and SR groups, respectively. Reductions in amyloid burden and percent of patients below the amyloid positivity threshold using an updated data cut (May 30, 2018) will be reported. Approximately 37 patients (MR-Pbo 12; MR-Gant 12; SR 13) will have their OLE 24 month PET scan for this analysis, not accounting for patient drop-out. Conclusions:Updated findings are expected to confirm preliminary results and show continued reduction in amyloid burden with ongoing treatment up to 24 months. This work supports our planned Phase 3 program using high doses of gantenerumab. 1. Klein, CTAD 2017.

THE EFFECT OF LOW DOSES OF GANTENERUMAB ON AMYLOID AND TAU BIOMARKERS IN CEREBROSPINAL FLUID (CSF) IN THE MARGUERITE ROAD STUDY

doses of LY3002813 resulted in significant reductions in florbetapir F18 tracer uptake on PET by 3 months, with further reduction with repeat dosing over time. For the initial dosing cohorts, reductions in florbetapir F18 at 3 months were -11.8 (SD 21.1) centiloids after a single dose of 10 mg/kg IV (n1⁄47); -39.0 (SD 18.1) centiloids after a single dose of 20mg/kg IV (n1⁄47); and -44.5 (SD 24.3) centiloids for 10mg/kg IVadministered every two weeks (n1⁄410). In patients with up to 72 weeks of follow-up after completion of treatment, the reduced post-treatment florbetapir F18 PET SUVr levels were maintained, without returning to pre-dose baseline levels. Conclusions: LY3002813 demonstrates significant, rapid and sustained reduction in cortical amyloid plaque in Alzheimer’s patients.

Correction to: A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

Following publication of the original article [1], the author reported errors in the formatting of the table. The details of the errors are as follows:

LONGITUDINAL EFFECTS OF PARTIAL VOLUME CHANGES ON SUVR VALUES

Figure 2. Posterior prediction for the individual time shift in the testing data. Healthy individuals are generally displaced at the early stages of the pathology, while the predictions for MCI and AD patients are associated with respectively intermediate and late progression stages. NL: normal individuals, MCI: mild cognitive impairment, AD: Alzheimer’s patients. Healthy individuals are associated with the early stages of the pathology in both training and testing data, while MCI and AD are characterized by late stages (p<1e-4 for the group-wise comparison). The temporal cut-off based on the 10th quantile of the staging in the training AD population (t1⁄43.6 years) leads to a discrimination accuracy of 0.84 for MCI converters vs stable in the testing data.

ON EVALUATION OF TAU ACCUMULATIONS IN LONGITUDINAL STUDIES OF ALZHEIMER’S DISEASE (AD): IMPLICATIONS FROM A PET STUDY WITH [18F]RO6958948

A1 19 A2 8 A3 22 A4 21 ACCUMULATIONS IN LONGITUDINAL STUDIES OFALZHEIMER’S DISEASE (AD): IMPLICATIONS FROMAPET STUDYWITH [18F]RO6958948 Hiroto Kuwabara, Edilio Borroni, Robert A. Comley, Joshua Roberts, Kelly Kitzmiller, Paul B. Rosenberg, Madhav Thambisetty, Michael Honer, Gregory Klein, Lorena Gapasin, Luca Gobbi, Dean F. Wong, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Roche Pharmaceutical Research and Early Development, Basel, Switzerland; Abbvie Inc., Chicago, IL, USA. Contact e-mail: hkuwaba1@jhmi.edu