Use of flutemetamol F18-labeled positron emission tomography and other biomarkers to assess risk of clinical progression in patients with amnestic mild cognitive impairment

David A. Wolk, Carl Sadowsky, Beth Safirstein, Juha O. Rinne, Ranjan Duara, Richard Perry, Marc Agronin, Jose Gamez, Jiong Shi, Adrian Ivanoiu, Lennart Minthon, Zuzana Walker, Steen Hasselbalch, Clive Holmes, Marwan Sabbagh, Marilyn Albert, Adam Fleisher, Paul Loughlin, Eric Triau, Kirk FreyPeter Høgh, Andrea Bozoki, Roger Bullock, Eric Salmon, Gillian Farrar, Christopher J. Buckley, Michelle Zanette, Paul F. Sherwin, Andrea Cherubini, Fraser Inglis

Research output: Contribution to journalArticle

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-upwas 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.

Original languageEnglish (US)
Pages (from-to)1114-1123
Number of pages10
JournalJAMA Neurology
Volume75
Issue number9
DOIs
StatePublished - Sep 1 2018

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Positron-Emission Tomography
Biomarkers
Alzheimer Disease
Amyloid
Outcome Assessment (Health Care)
Cognitive Dysfunction
flutemetamol
Aptitude
Kaplan-Meier Estimate
Multicenter Studies
Cohort Studies
Logistic Models
Regression Analysis
Magnetic Resonance Imaging
Physicians
Research

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Use of flutemetamol F18-labeled positron emission tomography and other biomarkers to assess risk of clinical progression in patients with amnestic mild cognitive impairment. / Wolk, David A.; Sadowsky, Carl; Safirstein, Beth; Rinne, Juha O.; Duara, Ranjan; Perry, Richard; Agronin, Marc; Gamez, Jose; Shi, Jiong; Ivanoiu, Adrian; Minthon, Lennart; Walker, Zuzana; Hasselbalch, Steen; Holmes, Clive; Sabbagh, Marwan; Albert, Marilyn; Fleisher, Adam; Loughlin, Paul; Triau, Eric; Frey, Kirk; Høgh, Peter; Bozoki, Andrea; Bullock, Roger; Salmon, Eric; Farrar, Gillian; Buckley, Christopher J.; Zanette, Michelle; Sherwin, Paul F.; Cherubini, Andrea; Inglis, Fraser.

In: JAMA Neurology, Vol. 75, No. 9, 01.09.2018, p. 1114-1123.

Research output: Contribution to journalArticle

Wolk, DA, Sadowsky, C, Safirstein, B, Rinne, JO, Duara, R, Perry, R, Agronin, M, Gamez, J, Shi, J, Ivanoiu, A, Minthon, L, Walker, Z, Hasselbalch, S, Holmes, C, Sabbagh, M, Albert, M, Fleisher, A, Loughlin, P, Triau, E, Frey, K, Høgh, P, Bozoki, A, Bullock, R, Salmon, E, Farrar, G, Buckley, CJ, Zanette, M, Sherwin, PF, Cherubini, A & Inglis, F 2018, 'Use of flutemetamol F18-labeled positron emission tomography and other biomarkers to assess risk of clinical progression in patients with amnestic mild cognitive impairment', JAMA Neurology, vol. 75, no. 9, pp. 1114-1123. https://doi.org/10.1001/jamaneurol.2018.0894
Wolk, David A. ; Sadowsky, Carl ; Safirstein, Beth ; Rinne, Juha O. ; Duara, Ranjan ; Perry, Richard ; Agronin, Marc ; Gamez, Jose ; Shi, Jiong ; Ivanoiu, Adrian ; Minthon, Lennart ; Walker, Zuzana ; Hasselbalch, Steen ; Holmes, Clive ; Sabbagh, Marwan ; Albert, Marilyn ; Fleisher, Adam ; Loughlin, Paul ; Triau, Eric ; Frey, Kirk ; Høgh, Peter ; Bozoki, Andrea ; Bullock, Roger ; Salmon, Eric ; Farrar, Gillian ; Buckley, Christopher J. ; Zanette, Michelle ; Sherwin, Paul F. ; Cherubini, Andrea ; Inglis, Fraser. / Use of flutemetamol F18-labeled positron emission tomography and other biomarkers to assess risk of clinical progression in patients with amnestic mild cognitive impairment. In: JAMA Neurology. 2018 ; Vol. 75, No. 9. pp. 1114-1123.
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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-upwas 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.",
author = "Wolk, {David A.} and Carl Sadowsky and Beth Safirstein and Rinne, {Juha O.} and Ranjan Duara and Richard Perry and Marc Agronin and Jose Gamez and Jiong Shi and Adrian Ivanoiu and Lennart Minthon and Zuzana Walker and Steen Hasselbalch and Clive Holmes and Marwan Sabbagh and Marilyn Albert and Adam Fleisher and Paul Loughlin and Eric Triau and Kirk Frey and Peter H{\o}gh and Andrea Bozoki and Roger Bullock and Eric Salmon and Gillian Farrar and Buckley, {Christopher J.} and Michelle Zanette and Sherwin, {Paul F.} and Andrea Cherubini and Fraser Inglis",
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TY - JOUR

T1 - Use of flutemetamol F18-labeled positron emission tomography and other biomarkers to assess risk of clinical progression in patients with amnestic mild cognitive impairment

AU - Wolk, David A.

AU - Sadowsky, Carl

AU - Safirstein, Beth

AU - Rinne, Juha O.

AU - Duara, Ranjan

AU - Perry, Richard

AU - Agronin, Marc

AU - Gamez, Jose

AU - Shi, Jiong

AU - Ivanoiu, Adrian

AU - Minthon, Lennart

AU - Walker, Zuzana

AU - Hasselbalch, Steen

AU - Holmes, Clive

AU - Sabbagh, Marwan

AU - Albert, Marilyn

AU - Fleisher, Adam

AU - Loughlin, Paul

AU - Triau, Eric

AU - Frey, Kirk

AU - Høgh, Peter

AU - Bozoki, Andrea

AU - Bullock, Roger

AU - Salmon, Eric

AU - Farrar, Gillian

AU - Buckley, Christopher J.

AU - Zanette, Michelle

AU - Sherwin, Paul F.

AU - Cherubini, Andrea

AU - Inglis, Fraser

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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-upwas 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.

AB - 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-upwas 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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