David A Wolk1, Carl Sadowsky2, Beth Safirstein3, Juha O Rinne4,5, Ranjan Duara6, Richard Perry7, Marc Agronin8, Jose Gamez9, Jiong Shi10, Adrian Ivanoiu11, Lennart Minthon12, Zuzana Walker13,14, Steen Hasselbalch15, Clive Holmes16,17, Marwan Sabbagh18, Marilyn Albert19, Adam Fleisher20,21, Paul Loughlin22, Eric Triau23, Kirk Frey24, Peter Høgh25, Andrea Bozoki26, Roger Bullock27, Eric Salmon28, Gillian Farrar29, Christopher J Buckley29, Michelle Zanette30, Paul F Sherwin30, Andrea Cherubini31, Fraser Inglis32. 1. Department of Neurology, Penn Memory Center, University of Pennsylvania, Philadelphia. 2. Division of Neurology, Nova Southeastern University, Fort Lauderdale, Florida. 3. Division of Neurology, MD Clinical, Hallandale Beach, Florida. 4. Turku PET Centre, University of Turku, Turku, Finland. 5. Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland. 6. Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida. 7. Imperial College Healthcare National Health Service Trust Charing Cross Hospital, London, United Kingdom. 8. Mental Health and Clinical Research, Miami Jewish Health Systems, Miami, Florida. 9. Galiz Research, Miami Springs, Florida. 10. Barrows Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona. 11. Department of Neurology, Cliniques Universitaires St Luc, Brussels, Belgium. 12. Memory Clinic, Department of Clinical Sciences, Lund University, Malmö, Sweden. 13. Division of Psychiatry, University College London, London, United Kingdom. 14. Specialist Dementia and Frailty Service, Essex Partnership University Foundation Trust, Essex, United Kingdom. 15. Danish Dementia Research Centre, Rigshospitalet, Copenhagen University, Copenhagen, Denmark. 16. Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, United Kingdom. 17. Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom. 18. Banner Sun Health Research Institute, Sun City, Arizona. 19. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 20. Banner Alzheimer's Institute, Phoenix, Arizona. 21. Now with Eli Lilly and Company, Indianapolis, Indiana. 22. The Princess Margaret Hospital, Windsor, United Kingdom. 23. Neurologie Tervuursevest, Leuven, Belgium. 24. Department of Nuclear Medicine and Molecular Imaging, University of Michigan Health System, Ann Arbor. 25. Department of Neurology, Regional Dementia Research Centre, Copenhagen University Hospital, Roskilde, Denmark. 26. Department of Neurology, Michigan State University, East Lansing. 27. Kingshill Research Centre, Swindon, United Kingdom. 28. Cyclotron Research Centre, University of Liège, Liège, Belgium. 29. GE Healthcare Life Sciences, Amersham, Buckinghamshire, United Kingdom. 30. GE Healthcare Life Sciences, Marlborough, Massachusetts. 31. Institute of Molecular Bioimaging and Physiology, Rome, Italy. 32. Glasgow Memory Clinic, Glasgow, United Kingdom.
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.
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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