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 | Dementia and Cognitive Impairment | JAMA Neurology | JAMA Network
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Original Investigation
September 2018

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

Author Affiliations
  • 1Department of Neurology, Penn Memory Center, University of Pennsylvania, Philadelphia
  • 2Division of Neurology, Nova Southeastern University, Fort Lauderdale, Florida
  • 3Division of Neurology, MD Clinical, Hallandale Beach, Florida
  • 4Turku PET Centre, University of Turku, Turku, Finland
  • 5Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland
  • 6Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida
  • 7Imperial College Healthcare National Health Service Trust Charing Cross Hospital, London, United Kingdom
  • 8Mental Health and Clinical Research, Miami Jewish Health Systems, Miami, Florida
  • 9Galiz Research, Miami Springs, Florida
  • 10Barrows Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, Arizona
  • 11Department of Neurology, Cliniques Universitaires St Luc, Brussels, Belgium
  • 12Memory Clinic, Department of Clinical Sciences, Lund University, Malmö, Sweden
  • 13Division of Psychiatry, University College London, London, United Kingdom
  • 14Specialist Dementia and Frailty Service, Essex Partnership University Foundation Trust, Essex, United Kingdom
  • 15Danish Dementia Research Centre, Rigshospitalet, Copenhagen University, Copenhagen, Denmark
  • 16Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, United Kingdom
  • 17Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
  • 18Banner Sun Health Research Institute, Sun City, Arizona
  • 19Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 20Banner Alzheimer’s Institute, Phoenix, Arizona
  • 21Now with Eli Lilly and Company, Indianapolis, Indiana
  • 22The Princess Margaret Hospital, Windsor, United Kingdom
  • 23Neurologie Tervuursevest, Leuven, Belgium
  • 24Department of Nuclear Medicine and Molecular Imaging, University of Michigan Health System, Ann Arbor
  • 25Department of Neurology, Regional Dementia Research Centre, Copenhagen University Hospital, Roskilde, Denmark
  • 26Department of Neurology, Michigan State University, East Lansing
  • 27Kingshill Research Centre, Swindon, United Kingdom
  • 28Cyclotron Research Centre, University of Liège, Liège, Belgium
  • 29GE Healthcare Life Sciences, Amersham, Buckinghamshire, United Kingdom
  • 30GE Healthcare Life Sciences, Marlborough, Massachusetts
  • 31Institute of Molecular Bioimaging and Physiology, Rome, Italy
  • 32Glasgow Memory Clinic, Glasgow, United Kingdom
JAMA Neurol. 2018;75(9):1114-1123. doi:10.1001/jamaneurol.2018.0894
Key Points

Question  How can biomarkers be used to supplement clinical assessments in the workup of patients with amnestic mild cognitive impairment?

Findings  In this multicenter cohort study assessing progression from amnestic mild cognitive impairment to probable Alzheimer disease after flutemetamol F 18–labeled positron emission tomography, patients with β-amyloid–positive scans had approximately 2.5 times the risk of progressing to probable Alzheimer disease within 3 years compared with those with negative scan results. Adding the biomarkers of hippocampal volume and cognitive status to the model increased the risk of progression to 8.5:1 during the same observation period.

Meaning  Biomarker combinations may have more utility than single diagnostic tests to assist physicians in assessing the risk of future cognitive decline.


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.