Chronic divalproex sodium use and brain atrophy in Alzheimer disease

Fleisher, Adam; Truran, Diana; T., J.; Langbaum, Jessica B.; Aisen, Paul S.; Cummings, Jeffrey L.; Jack, Clifford R.; Weiner, Myron; Thomas, Ronald G.; Schneider, Lon S.; Tariot, Pierre N.

doi:10.1212/wnl.0b013e318230a16c

Cited by 155 publications

(95 citation statements)

References 41 publications

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“…The majority of trials (n = 94) used at least one cognitive outcome, 25,27-29, 51,52,55,57,64,66,68,75,78,[86][87][88][89][90][91][92][93]97,104,106,107,110,112,115,118,119,121,123,125,126,130,131,133,134,[137][138][139][140]143,145,146 with a variety of 16 measures used. ADLs were measured in 55 trials, using 12 measures.…”

Section: Published Trialsmentioning

confidence: 99%

“…ADLs were measured in 55 trials, using 12 measures. 27,28,33,37,41,45,46,49,51,52,54,55,57,59,61,63,64,66,68,77,78,81,[85][86][87][88][89][90]92,97,104,[106][107][108][110][111][112]114,115,118,119,[121][122][123][124][125]128,134,135,137,138,[142][143][144][145] Biological markers were measured in 51 trials using a variety of nine biological t...…”

Section: Published Trialsmentioning

confidence: 99%

“…29,31,33,37,40,43,47,[53][54][55]59,63,66,[68][69][70][71]73,77,78,81,85,86,89,93,95,96,98,101,[103][104][105][109][110][111][112][113]115,116,121,122,[129][130][131][132]137,[139][140][141]144,145 Eleven of the published trials measured quality of life, using one of three outcomes. 28,33,66,68,78,…”

Section: Published Trialsmentioning

confidence: 99%

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Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Webster

Groskreutz

Grinbergs-Saull

et al. 2017

Health Technol Assess

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Background: There is currently no disease-modifying treatment available to halt or delay the progression of the disease pathology in dementia. An agreed core set of the best-available and most appropriate outcomes for disease modification would facilitate the design of trials and ensure consistency across disease modification trials, as well as making results comparable and meta-analysable in future trials. Objectives: To agree a set of core outcomes for disease modification trials for mild to moderate dementia with the UK dementia research community and patient and public involvement (PPI). Data sources: We included disease modification trials with quantitative outcomes of efficacy from (1) references from related systematic reviews in workstream 1; (2) searches of the Cochrane Dementia and Cognitive Improvement Group study register, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Latin American and Caribbean Health Sciences Literature and PsycINFO on 11 December 2015, and clinical trial registries [International Standard Randomised Controlled Trial Number (ISRCTN) and clinicaltrials.gov] on 22 and 29 January 2016; and (3) hand-searches of reference lists of relevant systematic reviews from database searches. Review methods: The project consisted of four workstreams. (1) We obtained related core outcome sets and work from co-applicants. (2) We systematically reviewed published and ongoing disease modification trials to identify the outcomes used in different domains. We extracted outcomes used in each trial, recording how many used each outcome and with how many participants. We divided outcomes into the domains measured and searched for validation data. (3) We consulted with PPI participants about recommended outcomes. (4) We presented all the synthesised information at a conference attended by the wider body of National Institute for Health Research (NIHR) dementia researchers to reach consensus on a core set of outcomes. Results: We included 149 papers from the 22,918 papers screened, referring to 125 individual trials. Eighty-one outcomes were used across trials, including 72 scales [31 cognitive, 12 activities of daily living (ADLs), 10 global, 16 neuropsychiatric and three quality of life] and nine biological techniques. We consulted with 18 people for PPI. The conference decided that only cognition and biological markers are core measures of disease modification. Cognition should be measured by the Mini Mental State Examination (MMSE) or the Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog), and brain changes through structural magnetic resonance imaging (MRI) in a subset of participants. All other domains are important but not core. We recommend using the Neuropsychiatric Inventory for neuropsychiatric symptoms: the Disability Assessment for Dementia for ADLs, the Dementia Quality of Life Measure for quality of life and the Clinical Dementia Rating scale to measure dementia globally. Limitations: Most of the trials inclu...

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Section: Published Trialsmentioning

confidence: 99%

Section: Published Trialsmentioning

confidence: 99%

See 1 more Smart Citation

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Webster

Groskreutz

Grinbergs-Saull

et al. 2017

Health Technol Assess

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“…Our findings are consistent with pseudoatrophic brain changes associated with valproate use that have been reported in isolated epilepsy cases, 1 as well as atrophy associated with valproate use in Alzheimer disease. 5 Cerebral volume decreases have also been observed in rats exposed to valproate in utero. 6 When we compared group B past valproate users with patients with epilepsy who had Figure 2 Volume and cortical thickness in valproate epilepsy cases, nonvalproate epilepsy cases, and controls Epilepsy patients taking valproate (1VPA) have reduced brain volume, white matter volume, and parietal lobe cortical thickness relative to epilepsy patients not on valproate (2VPA) and healthy controls.…”

mentioning

confidence: 97%

Sodium valproate use is associated with reduced parietal lobe thickness and brain volume

2013

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Sodium valproate use is associated with reduced parietal lobe thickness and brain volume ABSTRACT Objective: We hypothesized that total brain volume, white matter volume, and lobar cortical thickness would be different in epilepsy patients. We studied valproate relative to nonvalproate by using patients with epilepsy and healthy controls.Methods: Patients with focal intractable epilepsy from a tertiary epilepsy center were the primary group for analysis. A confirmatory analysis was carried out in an independent group of subjects imaged as part of a community-based study of childhood-onset epilepsy. Total brain volume; white matter volume; and frontal, parietal, occipital, and temporal lobe thickness were measured by processing whole-brain T1-weighted MRI using FreeSurfer 5.1.Results: Total brain volume, white matter volume, and parietal thickness were reduced in the valproate group relative to controls and nonvalproate users (valproate, n 5 9; nonvalproate, n 5 27; controls, n 5 45; all male). These findings were confirmed in an independent group (valproate, n 5 7; nonvalproate, n 5 70; controls, n 5 20; all male).Conclusions: Sodium valproate use in epilepsy is associated with parietal lobe thinning, reduced total brain volume, and reduced white matter volume. Level of evidence:This study provides Class IV evidence that use of valproate in epilepsy is associated with reduced parietal lobe thickness, total brain volume, and white matter volume.

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“…GSK3β is the main enzyme involved in tau hyperphosphorylation, and lithium and valproate are both drugs that inhibit GSK3β and reduce tau phosphorylation in animal models [117]. Unexpectedly, valproate impaired the cognitive and functional status, and it was also associated with a reduced brain volume in patients with AD receiving the drug in clinical trials [118]. Lithium is neuroprotective in animal models of AD, not only via the inhibition of GSK-3β but also through the remodeling of Aβ plaques, leading to a decrease in the number of dystrophic axons, reduced neuronal degeneration and improved cognitive scores in AD mice [119,120].…”

Section: Update On Dementiamentioning

confidence: 99%

Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease

Torres¹,

Busquets²,

Escribá³

2016

Update on Dementia

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Alzheimer's disease (AD) is a neurodegenerative disorder that causes severe and progressive cognitive impairment. The discovery of specific mutations related to AD supported the amyloid cascade hypothesis, which postulates that the accumulation of the amyloid-β (Aβ) peptide triggers neuronal death and dementia. However, most drugs that aim to prevent Aβ accumulation or tau phosphorylation have consistently failed in clinical trials. This would suggest that the amyloid pathology lies downstream of (an)other cellular event(s) that is/are responsible for AD pathogenesis. In this context, several lipid alterations have been described in the brain and in peripheral fluids of patients with AD, suggesting the involvement of lipids in the etiology of this condition. Indeed, the central nervous system (CNS) has the highest lipid content in the body, next to adipose tissue, and it is thought that normalization of brain membrane lipid levels would revert AD-related pathogenic events. In this sense, novel hydroxylated derivatives of docosahexaenoic acid (DHA) such as natural resolvins or synthetic hydroxy-DHA (HDHA, DHALifort) can modulate membrane lipid composition and show remarkable beneficial effects on AD hallmarks, such as prevention of amyloid production and tau phosphorylation, and cognitive restoration in animal models. Therefore, normalization of the neuronal lipid environment by hydroxyl-DHA and/or other lipids may constitute a promising therapy for AD treatment, memory loss and, possibly, other types of dementia.

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Chronic divalproex sodium use and brain atrophy in Alzheimer disease

Cited by 155 publications

References 41 publications

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations

Sodium valproate use is associated with reduced parietal lobe thickness and brain volume

Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease

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