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Chronic divalproex sodium use and brain atrophy in Alzheimer disease.

ABSTRACT: 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.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.There were no baseline differences between active treatment and placebo groups in age, education, brain volumes, clinical rating scores, or APOE ?4 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.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.

SUBMITTER: Fleisher AS

PROVIDER: S-EPMC3179645 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Chronic divalproex sodium use and brain atrophy in Alzheimer disease.

Fleisher A S AS Truran D D Mai J T JT Langbaum J B S JB Aisen P S PS Cummings J L JL Jack C R CR Weiner M W MW Thomas R G RG Schneider L S LS Tariot P N PN

Neurology 20110914 13

<h4>Objective</h4>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.<h4>Methods</h4>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 v ...[more]

PMID: 21917762

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Project description:CONTEXT:Agitation and psychosis are common in Alzheimer disease and cause considerable morbidity. We attempted to delay or to prevent agitation and psychosis with the use of divalproex sodium (valproate). OBJECTIVE:To determine whether treatment with valproate could delay or prevent emergence of agitation or psychosis. DESIGN, SETTING, AND PATIENTS:A multicenter, randomized, double-blind, placebo-controlled trial of flexible-dose valproate in 313 (of 513 screened) individuals with moderate Alzheimer disease who had not yet experienced agitation or psychosis. The study was conducted from November 1, 2005, through March 31, 2009, at 46 sites in the United States. INTERVENTION:Participants were randomly assigned to valproate treatment at a target dose of 10 to 12 mg per kilogram of body weight per day or identical-appearing placebo for 24 months followed by a 2-month period of single-blind placebo treatment. MAIN OUTCOME MEASURE:Time to emergence of clinically significant agitation or psychosis. RESULTS:A total of 122 participants (59 receiving valproate and 63 receiving placebo) completed 24 months of treatment while taking study medication; 42 (27 receiving valproate and 15 receiving placebo) reached 24 months having discontinued study medication; 150 reached month 26. There was no difference between groups in time to emergence of agitation or psychosis (Cox proportional hazard ratio, 0.96; P = .88). There was no difference between groups in change on any secondary outcome. The valproate group had higher rates of somnolence, gait disturbance, tremor, diarrhea, and weakness. Eighty-eight participants underwent magnetic resonance imaging scans at baseline and 12 months; the valproate group showed greater loss in hippocampal and whole-brain volume, accompanied by greater ventricular expansion (P < .001). CONCLUSION:Valproate treatment did not delay emergence of agitation or psychosis or slow cognitive or functional decline in patients with moderate Alzheimer disease and was associated with significant toxic effects.

Project description:ObjectiveTo test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline.MethodsAmyloid-positive participants with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n = 229) and 2-year clinical follow-up (n = 100) were included. AD subtypes (hippocampal sparing [HpSpMRI], limbic predominant [LPMRI], typical AD [tADMRI]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models.ResultsWhen participants were divided categorically, the HpSpMRI group showed significantly more AD-like hypometabolism on 18F-fluorodeoxyglucose-PET (p < 0.05) and poorer baseline executive function (p < 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSpMRI also showed faster subsequent clinical decline than participants with LPMRI on the Alzheimer's Disease Assessment Scale, 13-Item Subscale (ADAS-Cog13), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p < 0.05) and tADMRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p < 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog13 score (p < 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy.ConclusionsAD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation.

Project description:ImportanceMeasures of neuronal loss are likely good surrogates for clinical and radiological disease progression in Alzheimer disease (AD). Cerebrospinal fluid (CSF) markers of neuronal injury or neurodegeneration may offer usefulness in predicting disease progression and guiding outcome assessments and prognostic decisions in clinical trials of disease-modifying therapies. Visinin-like protein 1 (VILIP-1) has demonstrated potential usefulness as a marker of neuronal injury in AD.ObjectiveTo investigate the usefulness of CSF VILIP-1, tau, p-tau181, and Aβ42 levels in predicting rates of whole-brain and regional atrophy in early AD and cognitively normal control subjects over time.Design, setting, and participantsLongitudinal observational study of brain atrophy in participants with early AD and cognitively normal controls. Study participants had baseline CSF biomarker measurements and longitudinal magnetic resonance imaging assessments for a mean follow-up period of 2 to 3 years. Mixed linear models assessed the ability of standardized baseline CSF biomarker measures to predict rates of whole-brain and regional atrophy over the follow-up period. The setting was The Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St Louis. Participants (mean age, 72.6 years) were individuals with a clinical diagnosis of very mild AD (n = 23) and cognitively normal controls (n = 64) who were enrolled in longitudinal studies of healthy aging and dementia. The study dates were 2000 to 2010.Main outcomes and measuresCorrelations between baseline CSF biomarker measures and rates of whole-brain or regional atrophy in the AD and control cohorts over the follow-up period.ResultsBaseline CSF VILIP-1, tau, and p-tau181 levels (but not Aβ42 levels) predicted rates of whole-brain and regional atrophy in AD over the follow-up period. Baseline CSF VILIP-1 levels predicted whole-brain (P = .006), hippocampal (P = .01), and entorhinal (P = .001) atrophy rates at least as well as tau and p-tau181 in early AD. Cognitively normal controls whose CSF VILIP-1, tau, or p-tau181 levels were in the upper tercile had higher rates of whole-brain (P = .02, P = .003, and P = .02, respectively), hippocampal (P = .001, P = .01, and P = .02, respectively), and entorhinal (P = .007, P = .01, and P = .01, respectively) atrophy compared with those whose levels were in the lower 2 terciles.Conclusions and relevanceCerebrospinal fluid VILIP-1 levels predict rates of whole-brain and regional atrophy similarly to tau and p-tau181 and may provide a useful CSF biomarker surrogate for neurodegeneration in early symptomatic and preclinical AD.

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Chronic divalproex sodium use and brain atrophy in Alzheimer disease.

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Chronic divalproex sodium use and brain atrophy in Alzheimer disease.

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