Chronic divalproex sodium use and brain atrophy in Alzheimer disease

A. S. Fleisher, D. Truran, J. T. Mai, J. B S Langbaum, P. S. Aisen, J. L. Cummings, Clifford R Jr. Jack, M. W. Weiner, R. G. Thomas, L. S. Schneider, P. N. Tariot

Research output: Contribution to journalArticle

72 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1263-1271
Number of pages9
JournalNeurology
Volume77
Issue number13
DOIs
StatePublished - Sep 27 2011
Externally publishedYes

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Valproic Acid
Atrophy
Alzheimer Disease
Brain
Placebos
Alzheimer's Disease
Age Groups
Magnetic Resonance Imaging
Education
Placebo
Therapeutics
Rating

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Fleisher, A. S., Truran, D., Mai, J. T., Langbaum, J. B. S., Aisen, P. S., Cummings, J. L., ... Tariot, P. N. (2011). Chronic divalproex sodium use and brain atrophy in Alzheimer disease. Neurology, 77(13), 1263-1271. https://doi.org/10.1212/WNL.0b013e318230a16c

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, Clifford R Jr.; 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 journalArticle

Fleisher, AS, Truran, D, Mai, JT, Langbaum, JBS, Aisen, PS, Cummings, JL, Jack, CRJ, Weiner, MW, Thomas, RG, Schneider, LS & Tariot, PN 2011, 'Chronic divalproex sodium use and brain atrophy in Alzheimer disease', Neurology, vol. 77, no. 13, pp. 1263-1271. https://doi.org/10.1212/WNL.0b013e318230a16c
Fleisher AS, Truran D, Mai JT, Langbaum JBS, Aisen PS, Cummings JL et al. Chronic divalproex sodium use and brain atrophy in Alzheimer disease. Neurology. 2011 Sep 27;77(13):1263-1271. https://doi.org/10.1212/WNL.0b013e318230a16c
Fleisher, A. S. ; Truran, D. ; Mai, J. T. ; Langbaum, J. B S ; Aisen, P. S. ; Cummings, J. L. ; Jack, Clifford R Jr. ; Weiner, M. W. ; Thomas, R. G. ; Schneider, L. S. ; Tariot, P. N. / Chronic divalproex sodium use and brain atrophy in Alzheimer disease. In: Neurology. 2011 ; Vol. 77, No. 13. pp. 1263-1271.
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AU - Cummings, J. L.

AU - Jack, Clifford R Jr.

AU - Weiner, M. W.

AU - Thomas, R. G.

AU - Schneider, L. S.

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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.

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