Juhan Reimand1,2,3, Arno de Wilde4, Charlotte E Teunissen5, Marissa Zwan4, Albert D Windhorst6, Ronald Boellaard6, Frederik Barkhof6,7, Wiesje M van der Flier4,8, Philip Scheltens4, Bart N M van Berckel6, Rik Ossenkoppele4,9, Femke Bouwman4. 1. Department of Neurology & Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. jreimand@gmail.com. 2. Department of Health Technologies, Tallinn University of Technology, Tallinn, Estonia. jreimand@gmail.com. 3. Radiology Centre, North Estonia Medical Centre, Tallinn, Estonia. jreimand@gmail.com. 4. Department of Neurology & Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. 5. Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. 6. Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. 7. Centre for Medical Image Computing, Medical Physics and Biomedical Engineering, UCL, London, UK. 8. Department of Epidemiology & Biostatistics, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. 9. Clinical Memory Research Unit, Lund University, Lund, Sweden.
Abstract
BACKGROUND: Amyloid-β PET and CSF Aβ42 yield discordant results in 10-20% of memory clinic patients, possibly providing unique information. Although the predictive power of demographic, clinical, genetic, and imaging features for amyloid positivity has previously been investigated, it is unknown whether these features differentially predict amyloid-β status based on PET or CSF or whether this differs by disease stage. METHODS: We included 768 patients (subjective cognitive decline (SCD, n = 194), mild cognitive impairment (MCI, n = 127), dementia (AD and non-AD, n = 447) with amyloid-β PET and CSF Aβ42 measurement within 1 year. Ninety-seven (13%) patients had discordant PET/CSF amyloid-β status. We performed parallel random forest models predicting separately PET and CSF status using 17 patient features (demographics, APOE4 positivity, CSF (p)tau, cognitive performance, and MRI visual ratings) in the total patient group and stratified by syndrome diagnosis. Thereafter, we selected features with the highest variable importance measure (VIM) as input for logistic regression models, where amyloid status on either PET or CSF was predicted by (i) the selected patient feature and (ii) the patient feature adjusted for the status of the other amyloid modality. RESULTS: APOE4, CSF tau, and p-tau had the highest VIM for PET and CSF in all groups. In the amyloid-adjusted logistic regression models, p-tau was a significant predictor for PET-amyloid in SCD (OR = 1.02 [1.01-1.04], pFDR = 0.03), MCI (OR = 1.05 [1.02-1.07], pFDR < 0.01), and dementia (OR = 1.04 [1.03-1.05], pFDR < 0.001), but not for CSF-amyloid. APOE4 (OR = 3.07 [1.33-7.07], punc < 0.01) was associated with CSF-amyloid in SCD, while it was only predictive for PET-amyloid in MCI (OR = 9.44 [2.93, 30.39], pFDR < 0.01). Worse MMSE scores (OR = 1.21 [1.03-1.41], punc = 0.02) were associated to CSF-amyloid status in SCD, whereas worse memory (OR = 1.17 [1.05-1.31], pFDR = 0.02) only predicted PET positivity in dementia. CONCLUSION: Amyloid status based on either PET or CSF was predicted by different patient features, and this varied by disease stage, suggesting that PET-CSF discordance yields unique information. The stronger associations of both APOE4 carriership and worse memory z-scores with CSF-amyloid in SCD suggest that CSF-amyloid is more sensitive early in the disease course. The higher predictive value of CSF p-tau for a positive PET scan suggests that PET is more specific to AD pathology.
BACKGROUND: Amyloid-β PET and CSF Aβ42 yield discordant results in 10-20% of memory clinic patients, possibly providing unique information. Although the predictive power of demographic, clinical, genetic, and imaging features for amyloid positivity has previously been investigated, it is unknown whether these features differentially predict amyloid-β status based on PET or CSF or whether this differs by disease stage. METHODS: We included 768 patients (subjective cognitive decline (SCD, n = 194), mild cognitive impairment (MCI, n = 127), dementia (AD and non-AD, n = 447) with amyloid-β PET and CSF Aβ42 measurement within 1 year. Ninety-seven (13%) patients had discordant PET/CSF amyloid-β status. We performed parallel random forest models predicting separately PET and CSF status using 17 patient features (demographics, APOE4 positivity, CSF (p)tau, cognitive performance, and MRI visual ratings) in the total patient group and stratified by syndrome diagnosis. Thereafter, we selected features with the highest variable importance measure (VIM) as input for logistic regression models, where amyloid status on either PET or CSF was predicted by (i) the selected patient feature and (ii) the patient feature adjusted for the status of the other amyloid modality. RESULTS:APOE4, CSFtau, and p-tau had the highest VIM for PET and CSF in all groups. In the amyloid-adjusted logistic regression models, p-tau was a significant predictor for PET-amyloid in SCD (OR = 1.02 [1.01-1.04], pFDR = 0.03), MCI (OR = 1.05 [1.02-1.07], pFDR < 0.01), and dementia (OR = 1.04 [1.03-1.05], pFDR < 0.001), but not for CSF-amyloid. APOE4 (OR = 3.07 [1.33-7.07], punc < 0.01) was associated with CSF-amyloid in SCD, while it was only predictive for PET-amyloid in MCI (OR = 9.44 [2.93, 30.39], pFDR < 0.01). Worse MMSE scores (OR = 1.21 [1.03-1.41], punc = 0.02) were associated to CSF-amyloid status in SCD, whereas worse memory (OR = 1.17 [1.05-1.31], pFDR = 0.02) only predicted PET positivity in dementia. CONCLUSION: Amyloid status based on either PET or CSF was predicted by different patient features, and this varied by disease stage, suggesting that PET-CSF discordance yields unique information. The stronger associations of both APOE4 carriership and worse memory z-scores with CSF-amyloid in SCD suggest that CSF-amyloid is more sensitive early in the disease course. The higher predictive value of CSF p-tau for a positive PET scan suggests that PET is more specific to AD pathology.
Authors: Jonathan Graff-Radford; David T Jones; Heather J Wiste; Petrice M Cogswell; Stephen D Weigand; Val Lowe; Benjamin D Elder; Prashanthi Vemuri; Argonde Van Harten; Michelle M Mielke; David S Knopman; Neill R Graff-Radford; Ronald C Petersen; Clifford R Jack; Jeffrey L Gunter Journal: Neurobiol Aging Date: 2021-11-01 Impact factor: 4.673
Authors: Sean A P Clouston; Charles B Hall; Minos Kritikos; David A Bennett; Steven DeKosky; Jerri Edwards; Caleb Finch; William C Kreisl; Michelle Mielke; Elaine R Peskind; Murray Raskind; Marcus Richards; Richard P Sloan; Avron Spiro; Neil Vasdev; Robert Brackbill; Mark Farfel; Megan Horton; Sandra Lowe; Roberto G Lucchini; David Prezant; Joan Reibman; Rebecca Rosen; Kacie Seil; Rachel Zeig-Owens; Yael Deri; Erica D Diminich; Bernadette A Fausto; Sam Gandy; Mary Sano; Evelyn J Bromet; Benjamin J Luft Journal: Nat Rev Neurol Date: 2021-11-18 Impact factor: 42.937
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Authors: Argonde C van Harten; Heather J Wiste; Stephen D Weigand; Michelle M Mielke; Walter K Kremers; Udo Eichenlaub; Roy B Dyer; Alicia Algeciras-Schimnich; David S Knopman; Clifford R Jack; Ronald C Petersen Journal: Alzheimers Dement Date: 2021-07-26 Impact factor: 16.655
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