Abstract
Objective: We evaluated the effect of the divalproex sodium formulation of valproic acid on brain volumes using MRI in people with mild to moderate Alzheimer disease (AD) and assessed for changes associated with behavioral and cognitive effects. Methods: Eighty-nine of 313 participants randomized to divalproex or placebo in a 24-month, parallel-group trial received MRI scans at baseline and 12 months. Interval MRI annual percent changes in whole brain, ventricular, and hippocampal volumes were the primary outcomes of interest. Change from baseline in clinical outcomes was assessed at 6-month intervals. Results: There were no baseline differences between active treatment and placebo groups in age, education, brain volumes, clinical rating scores, or APOE ε4 carrier status. The group treated with divalproex showed a greater rate of decline in left and right hippocampal and brain volumes (-10.9% and -12.4% vs -5.6% and -6.3%, and -3.5% vs -1.4%, respectively), and a greater rate of ventricular expansion (24.5% vs 9.9%) (p < 0.001). Mini-Mental State Examination scores showed a more rapid decline with divalproex through month 12 (placebo = -2.0 ± 4.3, divalproex = -3.9 ± 4.0) (p = 0.037), although there were no changes on other cognitive, behavioral, or functional ratings at 12 and 24 months. Conclusions: Divalproex treatment was associated with accelerated brain volume loss over 1 year and perhaps with greater cognitive impairment. The long-term clinical effects of these changes are not known.
Original language | English (US) |
---|---|
Pages (from-to) | 1263-1271 |
Number of pages | 9 |
Journal | Neurology |
Volume | 77 |
Issue number | 13 |
DOIs | |
State | Published - Sep 27 2011 |
ASJC Scopus subject areas
- Clinical Neurology
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Chronic divalproex sodium use and brain atrophy in Alzheimer disease. / Fleisher, A. S.; Truran, D.; Mai, J. T.; Langbaum, J. B.S.; Aisen, P. S.; Cummings, J. L.; Jack, C. R.; Weiner, M. W.; Thomas, R. G.; Schneider, L. S.; Tariot, P. N.
In: Neurology, Vol. 77, No. 13, 27.09.2011, p. 1263-1271.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Chronic divalproex sodium use and brain atrophy in Alzheimer disease
AU - Fleisher, A. S.
AU - Truran, D.
AU - Mai, J. T.
AU - Langbaum, J. B.S.
AU - Aisen, P. S.
AU - Cummings, J. L.
AU - Jack, C. R.
AU - Weiner, M. W.
AU - Thomas, R. G.
AU - Schneider, L. S.
AU - Tariot, P. N.
N1 - Funding Information: Dr. Fleisher serves on scientific advisory boards for the NIH, Eli Lilly & Company, and Elan Corporation; has served as Guest Editor for Behavioral Neurology ; has served as a consultant for Elan Corporation, Pfizer Inc, Janssen, and Wyeth; and receives research support from Avid Radiopharmaceuticals, Inc., Eli Lilly and Company, and the NIH/NIA. Dr. Truran, Dr. Mai, and Dr. Langbaum report no disclosures. Dr. Aisen serves on a scientific advisory board for NeuroPhage and Novartis; serves on the editorial boards of BMC Medicine and Alzheimer's Research & Therapy ; is listed as inventor on a patent re: DHA therapy for apolipoprotein E4 negative Alzheimer's disease (potential royalties assigned in full to UCSD); serves as a consultant to Elan Corporation, Wyeth, Eisai Inc., Schering-Plough Corp., Bristol-Myers Squibb, Eli Lilly and Company, NeuroPhage, Merck & Co., Roche, Amgen, Genentech, Inc., Abbott, Pfizer Inc, Novartis, Bayer Schering Pharma, Astellas Pharma Inc., Dainippon Sumitomo Pharma, BioMarin Pharmaceutical Inc., Solvay Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo, AstraZeneca, Janssen, and Medivation, Inc.; receives research support from Pfizer Inc, Bayer Schering Pharma, Baxter International Inc., and the NIH/NIA; and has received stock options from Medivation, Inc. and NeuroPhage. Dr. Cummings has served on scientific advisory boards for Abbott, ACADIA Pharmaceuticals, Accera, Inc., Adamas Pharmaceuticals, Anavex Life Sciences Corp., Astellas Pharma Inc., Avanir Pharmaceuticals, Baxter International Inc., Bristol-Myers Squibb, CoMentis, Inc., Eisai Inc., Elan Corporation, EnVivo Pharmaceuticals, Forest Laboratories, Inc., Genentech, Inc., GlaxoSmithKline, Janssen, Eli Lilly and Company, Lundbeck Inc., Medivation, Inc., Medtronic, Inc., Merck Serono, Merz Pharmaceuticals, LLC, Myriad Genetics, Inc., Neuren Pharmaceuticals Limited, Neurokos, Novartis, Noven Pharmaceuticals, Inc., Orion Corporation Pfizer Inc, Prana Biotechnology Limited, QR Pharma, Inc., reMYND, Schering-Plough Corp., Signum Biosciences, Sonexa Therapeutics, Inc., Takeda Pharmaceutical Company Limited, Wyeth, and Toyama Chemical, Co., Ltd.; has received funding for travel and speaker honoraria from Abbott, Astellas Pharma Inc., Avanir Pharmaceuticals, Baxter International Inc., Bristol-Myers Squibb, Genentech, Inc., Lundbeck Inc., Novartis, and Pfizer Inc.; serves on the editorial boards of Psychogeriatrics, Practical Neurology, Dementia and Geriatric Cognitive Disorders, Internal Medicine Thailand, Cognitive and Behavioral Neurology, Middle-Eastern Journal of Age and Aging, Middle-Eastern Journal of Family Medicine, Clinical Neurology and Neurosurgery, Translational Neuroscience, Clinical Trial Magnifier, Translational Neuroscience , and Neuroscience Pathways ; serves as a consultant for Ambassador Nursing Homes Silverado Assisted Living; serves on speakers' bureaus for Eisai Inc., Forest Laboratories, Inc., Janssen, Novartis, Pfizer Inc, and Lundbeck Inc.; receives research support from the NIH/NIA and the Sidell-Kagan Foundation; owns stock in ADAMAS, Prana Biotechnology Limited, Sonexa Therapeutics, Inc., MedAvante, Inc., NeuroTrax, Neurokos, and QR Pharma, Inc.; receives license fee payments for use of the Neuropsychiatric Inventory; and has provided expert witness consultation in medico-legal cases. Dr. Jack serves on scientific advisory boards for Elan/Janssen AI, Eli Lilly & Company, GE Healthcare, and Eisai Inc.; receives research support from Baxter International Inc., Allon Therapeutics, Inc., Pfizer Inc, the NIH/NIA, and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation; and holds stock/stock options in Johnson & Johnson. Dr. Weiner serves on scientific advisory boards for Bayer Schering Pharma, Eli Lilly and Company, CoMentis, Inc., Neurochem Inc, Eisai Inc., Avid Radiopharmaceuticals Inc., Aegis Therapies, Genentech, Inc., Allergan, Inc., Lippincott Williams & Wilkins, Bristol-Myers Squibb, Forest Laboratories, Inc., Pfizer Inc, McKinsey & Company, Mitsubishi Tanabe Pharma Corporation, and Novartis; has received funding for travel from Nestlé and Kenes International and to attend conferences not funded by industry; serves on the editorial board of Alzheimer's & Dementia ; has received honoraria from the Rotman Research Institute and BOLT International; serves as a consultant for Elan Corporation; receives research support from Merck & Co., Radiopharmaceuticals Inc., the NIH, the Veterans Administration, and the State of California; and holds stock in Synarc and Elan Corporation. Dr. Thomas has served on a scientific advisory board for Myriad Genetics, Inc.; has served as a consultant for Medivation, Inc., Myriad Genetics, Inc., Bristol-Meyers Squibb, and Neurochem Inc.; and receives research support from the US Department of Defense and the NIH/NIA. Dr. Schneider served as an editor on the Cochrane Collaborations Dementia and Cognitive Improvement Group; serves on scientific advisory boards for AstraZeneca, AC Immune SA, Allon Therapeutics, Inc., Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck Serono, and Roche; serves on editorial boards for Alzheimer's & Dementia, Current Alzheimer's Research, International Journal of Geriatric Psychiatry, Psychogeriatrics , and BMC Psychiatry ; receives publishing royalties for Evidence-based Dementia Practice (Blackwell, 2003); serves as a consultant for Abbott, AC Immune SA, Allergan, Inc., Allon Therapeutics, Inc., Alzheimer Drug Discovery Foundation, AstraZeneca, Baxter International Inc., Bristol-Myers Squibb, Elan Corporation, Eli Lilly and Company, Exonhit, GlaxoSmithKline, Ipsen, Johnson & Johnson, Myriad Genetics, Inc., MedAvante, Inc., Merck Serono, Novartis, Pfizer Inc, Roche, Servier, Targacept, Inc., Toyama Chemical, Co., Ltd., Accera, Inc., Forest Laboratories, Inc., Lundbeck Inc., Medivation, Inc., sanofi-aventis, Schering-Plough Corp., Schwabe Pharma, Teva Pharmaceutical Industries Ltd., Voyager Pharmaceutical Corporation, Wyeth, and Transition Therapeutics Inc.; receives research support from AstraZeneca, Elan Pharmaceuticals, Forest Laboratories, Inc., Johnson & Johnson, Myriad Genetics, Inc., Takeda Pharmaceutical Company Limited, Wyeth, Baxter, Eli Lilly and Company, Novartis, Pfizer, the NIH (NIA, NIMH), and the Alzheimer's Association; and has prepared expert reports for medico-legal cases. Dr. Tariot serves/served on scientific advisory boards for ACADIA Pharmaceuticals, AC Immune SA, Allergan, Inc., Eisai Inc., Genentech, Inc., Novartis, sanofi-aventis, Schering-Plough Corp., Abbott, AstraZeneca, Bristol-Myers Squibb, Elan Corporation, GlaxoSmithKline, Eli Lilly and Company, Medivation, Inc., Merck Serono, Pfizer Inc, and Wyeth; has received funding for travel from Elan Corporation; serves on the editorial boards of CNS Spectrums, Expert Opinion on Investigational Drugs , and International Journal of Geriatric Psychiatry F1000 (Faculty of 1000 ); is author on a patent re: Biomarkers of neurodegenerative disease; has received speaker honoraria from Banner Health; serves as a consultant for Adamas Pharmaceuticals, Avid Radiopharmaceuticals, Inc., Baxter International Inc., EPIX Pharmaceuticals Inc, Forest Laboratories, Inc., MedAvante, Inc., Myriad Genetics, Inc., Roche, Transition Therapeutics Inc., Worldwide Clinical Trials, ACADIA Pharmaceuticals, AC Immune SA, Allergan, Inc., Eisai Inc., Genentech, Inc., Novartis, sanofi-aventis, Schering-Plough Corp., Abbott, AstraZeneca, Bristol Myers Squibb, Elan Corporation, GlaxoSmithKline, Eli Lilly and Company, Medivation, Inc., Merck Serono, Pfizer Inc, and Wyeth; receives research support from Baxter International Inc., Johnson & Johnson, Takeda Pharmaceutical Company Limited, Abbott, AstraZeneca, Avid Radiopharmaceuticals, Inc., Bristol-Myers Squibb, Elan Corporation, GlaxoSmithKline, Janssen, Eli Lilly and Company, Medivation, Inc., Merck Serono, Pfizer Inc, Toyama Chemical, Co., Ltd., Wyeth, the Alzheimer's Association, and the Arizona Department of Health; and holds stock options in MedAvante, Inc. and Adamas Pharmaceuticals.
PY - 2011/9/27
Y1 - 2011/9/27
N2 - Objective: We evaluated the effect of the divalproex sodium formulation of valproic acid on brain volumes using MRI in people with mild to moderate Alzheimer disease (AD) and assessed for changes associated with behavioral and cognitive effects. Methods: Eighty-nine of 313 participants randomized to divalproex or placebo in a 24-month, parallel-group trial received MRI scans at baseline and 12 months. Interval MRI annual percent changes in whole brain, ventricular, and hippocampal volumes were the primary outcomes of interest. Change from baseline in clinical outcomes was assessed at 6-month intervals. Results: There were no baseline differences between active treatment and placebo groups in age, education, brain volumes, clinical rating scores, or APOE ε4 carrier status. The group treated with divalproex showed a greater rate of decline in left and right hippocampal and brain volumes (-10.9% and -12.4% vs -5.6% and -6.3%, and -3.5% vs -1.4%, respectively), and a greater rate of ventricular expansion (24.5% vs 9.9%) (p < 0.001). Mini-Mental State Examination scores showed a more rapid decline with divalproex through month 12 (placebo = -2.0 ± 4.3, divalproex = -3.9 ± 4.0) (p = 0.037), although there were no changes on other cognitive, behavioral, or functional ratings at 12 and 24 months. Conclusions: Divalproex treatment was associated with accelerated brain volume loss over 1 year and perhaps with greater cognitive impairment. The long-term clinical effects of these changes are not known.
AB - Objective: We evaluated the effect of the divalproex sodium formulation of valproic acid on brain volumes using MRI in people with mild to moderate Alzheimer disease (AD) and assessed for changes associated with behavioral and cognitive effects. Methods: Eighty-nine of 313 participants randomized to divalproex or placebo in a 24-month, parallel-group trial received MRI scans at baseline and 12 months. Interval MRI annual percent changes in whole brain, ventricular, and hippocampal volumes were the primary outcomes of interest. Change from baseline in clinical outcomes was assessed at 6-month intervals. Results: There were no baseline differences between active treatment and placebo groups in age, education, brain volumes, clinical rating scores, or APOE ε4 carrier status. The group treated with divalproex showed a greater rate of decline in left and right hippocampal and brain volumes (-10.9% and -12.4% vs -5.6% and -6.3%, and -3.5% vs -1.4%, respectively), and a greater rate of ventricular expansion (24.5% vs 9.9%) (p < 0.001). Mini-Mental State Examination scores showed a more rapid decline with divalproex through month 12 (placebo = -2.0 ± 4.3, divalproex = -3.9 ± 4.0) (p = 0.037), although there were no changes on other cognitive, behavioral, or functional ratings at 12 and 24 months. Conclusions: Divalproex treatment was associated with accelerated brain volume loss over 1 year and perhaps with greater cognitive impairment. The long-term clinical effects of these changes are not known.
UR - http://www.scopus.com/inward/record.url?scp=82255160648&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=82255160648&partnerID=8YFLogxK
U2 - 10.1212/WNL.0b013e318230a16c
DO - 10.1212/WNL.0b013e318230a16c
M3 - Article
C2 - 21917762
AN - SCOPUS:82255160648
VL - 77
SP - 1263
EP - 1271
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 13
ER -