Anna Rosenberg1, Alina Solomon2,3,4, Hilkka Soininen2,5, Pieter Jelle Visser6,7, Kaj Blennow8,9, Tobias Hartmann10, Miia Kivipelto2,3,4,11,12. 1. Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. anna.rosenberg@uef.fi. 2. Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. 3. Division of Clinical Geriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. 4. Theme Aging, Karolinska University Hospital, Stockholm, Sweden. 5. Neurocenter, Department of Neurology, Kuopio University Hospital, Kuopio, Finland. 6. Department of Psychiatry and Neuropsychology, Alzheimer Centre Limburg, University of Maastricht, Maastricht, Netherlands. 7. Department of Neurology, Alzheimer Centre, Amsterdam Neuroscience, VU University Medical Centre, Amsterdam, Netherlands. 8. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. 9. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 10. Deutsches Institut für Demenz Prävention (DIDP), Medical Faculty, and Department of Experimental Neurology, Saarland University, Homburg, Germany. 11. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. 12. Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK.
Abstract
BACKGROUND: To explore the utility of the International Working Group (IWG)-1 criteria in recruitment for Alzheimer's disease (AD) clinical trials, we applied the more recently proposed research diagnostic criteria to individuals enrolled in a randomized controlled prevention trial (RCT) and assessed their disease progression. METHODS: The multinational LipiDiDiet RCT targeted 311 individuals with IWG-1 defined prodromal AD. Based on centrally analyzed baseline biomarkers, participants were classified according to the IWG-2 and National Institute on Aging-Alzheimer's Association (NIA-AA) 2011 and 2018 criteria. Linear mixed models were used to investigate the 2-year change in cognitive and functional performance (Neuropsychological Test Battery NTB Z scores, Clinical Dementia Rating-Sum of Boxes CDR-SB) (criteria × time interactions; baseline score, randomization group, sex, Mini-Mental State Examination (MMSE), and age also included in the models). Cox models adjusted for randomization group, MMSE, sex, age, and study site were used to investigate the risk of progression to dementia over 2 years. RESULTS: In total, 88%, 86%, and 69% of participants had abnormal cerebrospinal fluid (CSF) β-amyloid, total tau, and phosphorylated tau, respectively; 64% had an A+T+N+ profile (CSF available for N = 107). Cognitive-functional decline appeared to be more pronounced in the IWG-2 prodromal AD, NIA-AA 2011 high and intermediate AD likelihood, and NIA-AA 2018 AD groups, but few significant differences were observed between the groups within each set of criteria. Hazard ratio (95% CI) for dementia was 4.6 (1.6-13.7) for IWG-2 prodromal AD (reference group no prodromal AD), 7.4 (1.0-54.7) for NIA-AA 2011 high AD likelihood (reference group suspected non-AD pathology SNAP), and 9.4 (1.2-72.7) for NIA-AA 2018 AD (reference group non-Alzheimer's pathologic change). Compared with the NIA-AA 2011 high AD likelihood group (abnormal β-amyloid and neuronal injury markers), disease progression was similar in the intermediate AD likelihood group (medial temporal lobe atrophy; no CSF available). CONCLUSIONS: Despite being less restrictive than the other criteria, the IWG-1 criteria reliably identified individuals with AD pathology. More pragmatic and easily applicable selection criteria might be preferred due to feasibility in certain situations, e.g., in multidomain prevention trials that do not specifically target β-amyloid/tau pathologies. TRIAL REGISTRATION: Netherlands Trial Register, NL1620 . Registered on 9 March 2009.
RCT Entities:
BACKGROUND: To explore the utility of the International Working Group (IWG)-1 criteria in recruitment for Alzheimer's disease (AD) clinical trials, we applied the more recently proposed research diagnostic criteria to individuals enrolled in a randomized controlled prevention trial (RCT) and assessed their disease progression. METHODS: The multinational LipiDiDiet RCT targeted 311 individuals with IWG-1 defined prodromal AD. Based on centrally analyzed baseline biomarkers, participants were classified according to the IWG-2 and National Institute on Aging-Alzheimer's Association (NIA-AA) 2011 and 2018 criteria. Linear mixed models were used to investigate the 2-year change in cognitive and functional performance (Neuropsychological Test Battery NTB Z scores, Clinical Dementia Rating-Sum of Boxes CDR-SB) (criteria × time interactions; baseline score, randomization group, sex, Mini-Mental State Examination (MMSE), and age also included in the models). Cox models adjusted for randomization group, MMSE, sex, age, and study site were used to investigate the risk of progression to dementia over 2 years. RESULTS: In total, 88%, 86%, and 69% of participants had abnormal cerebrospinal fluid (CSF) β-amyloid, total tau, and phosphorylated tau, respectively; 64% had an A+T+N+ profile (CSF available for N = 107). Cognitive-functional decline appeared to be more pronounced in the IWG-2 prodromal AD, NIA-AA 2011 high and intermediate AD likelihood, and NIA-AA 2018 AD groups, but few significant differences were observed between the groups within each set of criteria. Hazard ratio (95% CI) for dementia was 4.6 (1.6-13.7) for IWG-2 prodromal AD (reference group no prodromal AD), 7.4 (1.0-54.7) for NIA-AA 2011 high AD likelihood (reference group suspected non-AD pathology SNAP), and 9.4 (1.2-72.7) for NIA-AA 2018 AD (reference group non-Alzheimer's pathologic change). Compared with the NIA-AA 2011 high AD likelihood group (abnormal β-amyloid and neuronal injury markers), disease progression was similar in the intermediate AD likelihood group (medial temporal lobe atrophy; no CSF available). CONCLUSIONS: Despite being less restrictive than the other criteria, the IWG-1 criteria reliably identified individuals with AD pathology. More pragmatic and easily applicable selection criteria might be preferred due to feasibility in certain situations, e.g., in multidomain prevention trials that do not specifically target β-amyloid/tau pathologies. TRIAL REGISTRATION: Netherlands Trial Register, NL1620 . Registered on 9 March 2009.
Entities:
Keywords:
Alzheimer’s disease; Biomarkers; Cerebrospinal fluid; Disease progression; Early diagnosis; Prevention; Prodromal Alzheimer’s disease; Randomized controlled trial; Research criteria
Authors: Clifford R Jack; David S Knopman; William J Jagust; Ronald C Petersen; Michael W Weiner; Paul S Aisen; Leslie M Shaw; Prashanthi Vemuri; Heather J Wiste; Stephen D Weigand; Timothy G Lesnick; Vernon S Pankratz; Michael C Donohue; John Q Trojanowski Journal: Lancet Neurol Date: 2013-02 Impact factor: 44.182
Authors: Bruno Dubois; Harald Hampel; Howard H Feldman; Philip Scheltens; Paul Aisen; Sandrine Andrieu; Hovagim Bakardjian; Habib Benali; Lars Bertram; Kaj Blennow; Karl Broich; Enrica Cavedo; Sebastian Crutch; Jean-François Dartigues; Charles Duyckaerts; Stéphane Epelbaum; Giovanni B Frisoni; Serge Gauthier; Remy Genthon; Alida A Gouw; Marie-Odile Habert; David M Holtzman; Miia Kivipelto; Simone Lista; José-Luis Molinuevo; Sid E O'Bryant; Gil D Rabinovici; Christopher Rowe; Stephen Salloway; Lon S Schneider; Reisa Sperling; Marc Teichmann; Maria C Carrillo; Jeffrey Cummings; Cliff R Jack Journal: Alzheimers Dement Date: 2016-03 Impact factor: 21.566
Authors: Anja Soldan; Corinne Pettigrew; Anne M Fagan; Suzanne E Schindler; Abhay Moghekar; Christopher Fowler; Qiao-Xin Li; Steven J Collins; Cynthia Carlsson; Sanjay Asthana; Colin L Masters; Sterling Johnson; John C Morris; Marilyn Albert; Alden L Gross Journal: Neurology Date: 2019-03-06 Impact factor: 9.910
Authors: S C Burnham; P M Coloma; Q-X Li; S Collins; G Savage; S Laws; J Doecke; P Maruff; R N Martins; D Ames; C C Rowe; C L Masters; V L Villemagne Journal: J Prev Alzheimers Dis Date: 2019
Authors: Stephanie J B Vos; Frans Verhey; Lutz Frölich; Johannes Kornhuber; Jens Wiltfang; Wolfgang Maier; Oliver Peters; Eckart Rüther; Flavio Nobili; Silvia Morbelli; Giovanni B Frisoni; Alexander Drzezga; Mira Didic; Bart N M van Berckel; Andrew Simmons; Hilkka Soininen; Iwona Kłoszewska; Patrizia Mecocci; Magda Tsolaki; Bruno Vellas; Simon Lovestone; Cristina Muscio; Sanna-Kaisa Herukka; Eric Salmon; Christine Bastin; Anders Wallin; Arto Nordlund; Alexandre de Mendonça; Dina Silva; Isabel Santana; Raquel Lemos; Sebastiaan Engelborghs; Stefan Van der Mussele; Yvonne Freund-Levi; Åsa K Wallin; Harald Hampel; Wiesje van der Flier; Philip Scheltens; Pieter Jelle Visser Journal: Brain Date: 2015-02-17 Impact factor: 13.501
Authors: Clifford R Jack; David S Knopman; Stephen D Weigand; Heather J Wiste; Prashanthi Vemuri; Val Lowe; Kejal Kantarci; Jeffrey L Gunter; Matthew L Senjem; Robert J Ivnik; Rosebud O Roberts; Walter A Rocca; Bradley F Boeve; Ronald C Petersen Journal: Ann Neurol Date: 2012-04-09 Impact factor: 10.422
Authors: Hugo Botha; William G Mantyh; Jonathan Graff-Radford; Mary M Machulda; Scott A Przybelski; Heather J Wiste; Matthew L Senjem; Joseph E Parisi; Ronald C Petersen; Melissa E Murray; Bradley F Boeve; Val J Lowe; David S Knopman; Clifford R Jack; David T Jones Journal: Neurology Date: 2018-02-07 Impact factor: 9.910
Authors: S Sindi; C Thunborg; A Rosenberg; P Andersen; S Andrieu; L M Broersen; N Coley; C Couderc; C Z Duval; G Faxen-Irving; G Hagman; M Hallikainen; K Håkansson; J Lehtisalo; N Levak; F Mangialasche; J Pantel; E Kekkonen; A Rydström; A Stigsdotter-Neely; A Wimo; T Ngandu; H Soininen; T Hartmann; A Solomon; M Kivipelto Journal: J Prev Alzheimers Dis Date: 2022