Abstract
The International CTAD Task Force (TF) addressed challenges related to designing clinical trials for agitation in dementia, presenting accomplishments from the two previous TFs on neuropsychiatric symptoms (NPS). In addition, this TF proposed a paradigm shift in NPS assessment and management, presenting Mild Behavioral Impairment (MBI) as a clinical syndrome. MBI is marked by later-life emergent and persistent NPS in dementia-free older persons (ranging from cognitively unimpaired to subjective cognitive decline to mild cognitive impairment), which facilitates earlier detection and better prognostication of Alzheimer’s disease (AD). The TF has made the following recommendations for incorporation of NPS into AD preventative trials: (1) clinical trials targeting improvement in MBI symptoms should be undertaken; (2) treatment trials for MBI should be disease specific and confirm the diagnosis of participants using biomarkers; trials should include measures sensitive to cognitive changes in preclinical AD, which can serve as outcome measures, in addition to changes in biomarker levels; (3) as a first step, pharmacotherapeutic trials should address the full MBI complex as well as the specific symptoms/domains that constitute MBI; (4) clinical trials using problemadaptation psychotherapy to target affective MBI should be considered; and (5) MBI should be considered in AD trials of disease modifying therapies. The well-validated and widely-used MBI Checklist (MBI-C) is an appropriate symptom rating scale for these studies, as it was developed specifically to identify and measure MBI in dementia-free persons. Other scales such as the Neuropsychiatric Inventory (NPI) may be used, although administration at two timepoints may be necessary to operationalize the MBI criterion of symptom persistence.
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MS has received support from the National French Health Minister (DGOS): PREPS 2019, 19-0027; PBR has received support from the National Institute on Aging (AG054771, AG050515) as well as the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease. CL has received support from the National Institute on Aging (R01 AG052510; R01 AG031348P30 AG066507); Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease including significant contributions from the Richman Family Foundation, the Rick Sharp Alzheimer’s Foundation, the Sharp Family Foundation and others. ZI is funded by the Canadian Institutes of Health Research (BCA2633). He has also received support from the ADDF, Brain Canada, CCNA, Gordie Howe C.A.R.E.S, NIA, and Weston Foundation.
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Conflict of interest: The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. MS has served on advisory boards/consultancies Acadia, Otsuka, Avanir, Medesis Pharma, Servier, Eisai, Roche, Biogen, Lilly and Ethypharm. PBR has received research grants from the National Institutes of Aging, Alzheimer’s Clinical Trials Consortium, Richman Family Precision Medicine Center of Excellence on Alzheimer’s Disease, Eisai, Functional Neuromodulation, and Lilly; honoraria from GLG, Leerink, Cerevel, Cerevance, Bioxcel, Sunovion, Acadia, Medalink, Novo Nordisk, Noble Insights, TwoLabs, Otsuka, Lundbeck, Acadia, MedaCorp, ExpertConnect, HMP Global, Synaptogenix, and Neurology Week. CL has received support from Functional Neuromodulation, Ltd, Orion, Servier, Astellas, SVB Leerink, Roche, Avanir, Karuna, Maplight,Axsome, GW Research Limited, Merck, EXCIVA GmbH, Otsuka, and IntraCellular Therapies. DM is a full-time employee of Signant Health. MC has no disclosures. BV is an investigator in clinical trials sponsored by Biogen, Lilly, Roche, Eisai, Pfizer, Pierre Fabre Pharmaceuticals and the Toulouse University Hospital. He has served as SAB member for Biogen, Alzheon, Green Valley, Norvo Nordisk, Longeveron, Rejuvenate Biomed Clinical Pfizer, Eisai France, Advisory Board Meeting - but received no personal compensation. He has served as consultant and/or SAB member for Roche, Lilly, Eisai, TauX, Cerecin with personal compensation. CB has Grants and personal fees from Acadia, Lundbeck, Synexus, Novo Nordisk, and Enterin; and personal fees from Janssen, GW Pharma, TauRx, Biogen, Orion, Roche, Otsuka, Novartis, Eli Lilly, Suven, Sunovion, ADDEX and Exciva. SG has been a member of SAB for Alzheon, AmyriAD, Eisai Canada, EnigmaUSA, Lilly Canada, Medesis, Otsuka Canada, and TauRx, and has given lectures for Biogen Canada, and Lundbeck Korea. ZI has served on advisory boards/consultancies for Acadia, Biogen, Lundbeck, Otsuka, Roche, and the Canadian Agencies for Drugs and Technologies in Health and serves on the Government of Canada Ministerial Advisory Board for Dementia. He has received honoraria from Lundbeck/Otsuka and his institution has received fees from Acadia, Biogen, and Roche in lieu.
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Soto, M., Rosenberg, P., Ballard, C. et al. Neuropsychiatric Symptoms in AD: Clinical Trials Targeting Mild Behavioral Impairment: A Report from the International CTAD Task Force. J Prev Alzheimers Dis 11, 56–64 (2024). https://doi.org/10.14283/jpad.2023.125
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DOI: https://doi.org/10.14283/jpad.2023.125