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Multicenter Study
. 2018 Sep 1;75(9):1114-1123.
doi: 10.1001/jamaneurol.2018.0894.

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

David A Wolk  1 , Carl Sadowsky  2 , Beth Safirstein  3 , Juha O Rinne  4   5 , Ranjan Duara  6 , Richard Perry  7 , Marc Agronin  8 , Jose Gamez  9 , Jiong Shi  10 , Adrian Ivanoiu  11 , Lennart Minthon  12 , Zuzana Walker  13   14 , Steen Hasselbalch  15 , Clive Holmes  16   17 , Marwan Sabbagh  18 , Marilyn Albert  19 , Adam Fleisher  20   21 , Paul Loughlin  22 , Eric Triau  23 , Kirk Frey  24 , Peter Høgh  25 , Andrea Bozoki  26 , Roger Bullock  27 , Eric Salmon  28 , Gillian Farrar  29 , Christopher J Buckley  29 , Michelle Zanette  30 , Paul F Sherwin  30 , Andrea Cherubini  31 , Fraser Inglis  32
Affiliations
Multicenter Study

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

David A Wolk et al. JAMA Neurol. .

Abstract

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 β-amyloid positive vs those who were β-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 β-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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Wolk reported receiving grants and personal fees for consultation from GE Healthcare, Merck, Eli Lilly, and Jannsen during the conduct of the study; and receiving grants from Avid Radiopharmaceuticals, Eli Lilly, Merck, Functional Neuromodulation, and Biogen outside the submitted work. Dr Sadowsky reported receiving personal fees from Accera Advisory Board and Speaker’s Bureau; receiving personal fees from Lilly Advisory Board and Speaker’s Bureau; receiving personal fees from Novartis Advisory Board and Speaker’s Bureau; receiving grants from payment for clinical trials from Abbott, Lilly, Pfizer, GE Healthcare, Neuronix, Avanir, Tau RX, Wyeth, and Roche; receiving personal fees from Neuronix Advisory Board, outside the submitted work. Dr Rinne reported serving as a consultant for TEVA Finland Ltd and Clinical Research Services Turku Ltd. Dr Duara reported receiving grants from GE Healthcare during the conduct of the study, and receiving personal fees from GE Healthcare outside the submitted work. Dr Perry reported receiving personal fees for sponsored study from GE Healthcare, personal fees for serving on the Advisory Board from Eli Lilly, and personal fees for serving on the Advisory Board from Roche, outside the submitted work. Dr Agronin reported receiving research fees from GE Healthcare during the conduct of the study. Dr Ivanoiu reported receiving personal fees and nonfinancial support from GE Healthcare during the conduct of the study and receiving personal fees and nonfinancial support from GE Healthcare, outside the submitted work. Dr Walker reported receiving travel expenses from GE Healthcare during the conduct of the study and receiving personal fees from GE Healthcare, grants from GE Healthcare, and nonfinancial support from GE Healthcare outside the submitted work. Dr Sabbagh reported receiving grants from Takeda, grants from Neuronix, personal fees from Piramal, grants from Bayer, grants and personal fees from Lilly, grants from Functional Neuromodulation, grants from Roche, grants from Genentech, grants from Avid, grants from Navidea, and grants from Merck, outside the submitted work. Dr Fleisher reported receiving honoraria for consultations from Eli Lilly and Co, Merck, and Pfizer; receiving grants from the National Institute of Aging, Eli Lilly, and Avid Radiopharmaceuticals; reeiving personal fees from Eli Lilly, Grifols, Avid Radiopharmaceuticals, and Siemens, outside the submitted work; during the execution of this study, Dr Fleisher was a full-time employee of the Banner Alzheimer’s Institute; since April 7, 2014, and at the time of this submission, Dr Fleisher is a full-time employee of Eli Lilly and Co; Dr Fleisher also reported maintaining a voluntary faculty appointment at the University of California, San Diego. Dr Loughlin reported receiving grants from National Health Service UK National Institute of Health Research/Dementias and Neurodegeneration, during the conduct of the study; receiving grants from Servier and Eli Lilly, outside the submitted work; and in the 3 years prior to submission of this article chairing meetings sponsored by Lundbeck and attending an expert panel meeting for Nutricia, for all of which he received honorarium payments; and attending an academic meeting at which his attendance was sponsored by Lundbeck. Dr Frey reported receiving grants from GE Healthcare, during the conduct of the study and serving as a paid consultant for MIM Software Inc, Siemens, and Beyer Haring Pharma (Piramal). Dr Bozoki reported receiving grants from GE Healthcare during the conduct of the study. Dr Salmon reported serving as a scientific board member for GE Healthcare during the conduct of the study and serving as a scientific board member for Nutricia and GE Healthcare, outside the submitted work. Dr Farrar reported employment at GE Healthcare during the conduct of the study and outside the submitted work. Dr Buckley reported employment at GE Healthcare during the conduct of the study and outside the submitted work. Ms Zanette reported employment at GE Healthcare during the conduct of the study and outside the submitted work. Dr Sherwin reported employment at GE Healthcare during the conduct of the study and outside the submitted work. Dr Inglis reported receiving grants from GE Healthcare during the conduct of the study; and receiving grants from Abbott Laboratories, AbbVie, Eli Lilly, Eisai, Noscira, Genentech, Merck, Takeda, and Wyeth; receiving grants and personal fees from Pfizer and Roche, outside the submitted work.

Figures

Figure 1.
Figure 1.. Survival (Nonprogression) Probabilities Over Time for Patients With Positive or Negative Flutemetamol F 18–Labeled Positron Emission Tomographic Scans
Scan results assessed as positive or negative for β-amyloid by majority interpretation. Crosses are censored patients. Each vertical line marks 1 or more individuals who progressed to probable Alzheimer disease (pAD). The median time to progression to pAD was 928 days (95% CI, 760-1115) in the group with positive scan results but could not be estimated in the group with negative scan results, owing to a progression rate of less than 50%.
Figure 2.
Figure 2.. Survival Curves Based on β-Amyloid Status, Neurodegeneration, and Cognition
A, Survival curves by majority flutemetamol F 18 visual image interpretation (either β-amyloid positive [A+] or β-amyloid negative [A−]) and hippocampal volume (either neurodegeneration positive [N+] or neurodegeneration negative [N−]) combinations. The median time to progression to probable Alzheimer disease (pAD) was 911 days (95% CI, 735-1093) in the A+N+ group and 1092 days (95% CI, 730 to NE) in the A+N− group. Other groups could not be estimated owing to a progression rate of less than 50% during the course of the study. B, Survival curves by majority flutemetamol F 18 visual image interpretation (either A+ or A−), hippocampal volume (either N+ or N−), and severity of mild cognitive impairment (MCI) (early MCI [EMCI] or late MCI [LMCI]) combinations. The vertical order of the group labels corresponds to the probability of progression, least to highest. The median time to progression to pAD was 730 days (95% CI, 205 to NE) in the A+N−LMCI group, 900 days (95% CI, 630-926) in the A+N+LMCI group, 913 days (95% CI, 393 to NE) in the A−N+LMCI group, and 1097 days (95% CI, 925 to NE) in the A+N−EMCI group. The median time to progression to pAD for other groups were not able to be estimated owing to a progression rate of less than 50%; upper limits are not able to be estimated (NE) in some cases owing to sparse data. Crosses are censored patients.
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