RESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Agitación Psicomotora/tratamiento farmacológico , Trastornos Psicóticos/tratamiento farmacológico , Ácido Valproico/uso terapéutico , Anciano , Enfermedad de Alzheimer/complicaciones , Atrofia/patología , Encéfalo/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fármacos Neuroprotectores/efectos adversos , Modelos de Riesgos Proporcionales , Agitación Psicomotora/complicaciones , Agitación Psicomotora/prevención & control , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/prevención & control , Índice de Severidad de la Enfermedad , Ácido Valproico/efectos adversosRESUMEN
The molecular profiling of peripheral tissues, including circulating leukocytes, may hold promise in the discovery of biomarkers for diagnosing and treating neurodegenerative diseases, including Alzheimer's disease (AD). As a proof-of-concept, we performed a proteomics study on peripheral leukocytes from patients with AD both before and during treatment with divalproex sodium. Using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, we identified 10 differentially expressed proteins: two up-regulated proteins, 14-3-3 protein epsilon and peroxiredoxin 2; and eight down-regulated proteins, actin-interacting protein, mitogen activated protein kinase 1, beta actin, annexin A1, glyceraldehyde 3-phosphate dehydrogenase, transforming protein RhoA, acidic leucine-rich nuclear phosphoprotein 32 family member B, and a currently unidentified protein. A subset was validated on both the transcript and protein levels in normal human peripheral blood mononuclear cell cultures treated with valproic acid. These proteins comprise a number of functional classes that may be important to the biology of AD and to the therapeutic action of valproate. These data also suggest the potential of using peripheral leukocytes to monitor pharmaceutical action for neurodegenerative diseases.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Leucocitos/metabolismo , Proteoma/metabolismo , Ácido Valproico/administración & dosificación , Anciano , Anciano de 80 o más Años , Anticonvulsivantes/administración & dosificación , Células Cultivadas , Humanos , Leucocitos/efectos de los fármacos , Persona de Mediana EdadRESUMEN
OBJECTIVE: This paper provides a case study of 'reverse translational research', in which empirical clinical trials focused on relieving psychopathological symptoms of Alzheimer's disease (AD) ultimately led to mechanism-based trials addressing aspects of the underlying pathophysiology of Alzheimer's disease. AD is multi-dimensional in nature, characterized not only by cognitive and functional decline but by neuropsychiatric symptoms that develop commonly and are associated with considerable morbidity. There have been a large number of empirical trials of various pharmacological agents to reduce these symptoms, such as agitation. Although antipsychotics are used most frequently for agitation, the usual effect size is modest, and there is a range of tolerability and/or safety issues, leading to the hope that alternatives can be found. Furthermore, most clinical trials addressing psychopathology have not been mechanism-based and none have attempted an alternative approach, namely, to delay or prevent the emergence of psychopathology. FINDINGS: The evidence of clinical trials is reviewed regarding the safety, tolerability, and apparent efficacy of the mood stabilizers carbamazepine and valproate for agitation associated with AD. Possible mechanisms of action of valproate are reviewed, leading to the surprising conclusion that neuroprotective properties may account for some of its clinical effects. These mechanisms (including activation of wnt-dependent signaling and upregulation of bcl-2, among others) may be particularly relevant for long-term treatment of AD. CONCLUSIONS: These clinical and mechanistic findings were combined in the development of a novel clinical trial examining whether chronic valproate therapy can attenuate the clinical progression of AD, which will be implemented by the Alzheimer's Disease Cooperative Study. The design addresses valproate's potential to delay or prevent the onset of agitation in patients lacking agitation to begin with, as well as to slow progressive decline in cognition and daily functioning.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/psicología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Animales , Ensayos Clínicos como Asunto/métodos , Humanos , Trastornos del Humor/tratamiento farmacológico , Trastornos del Humor/metabolismo , Trastornos del Humor/psicología , Agitación Psicomotora/tratamiento farmacológico , Agitación Psicomotora/metabolismo , Agitación Psicomotora/psicología , Psicotrópicos/uso terapéutico , Ácido Valproico/uso terapéuticoRESUMEN
Female Sprague-Dawley rats received approximately 300 mg/kg per day of choline chloride through their drinking water on days 11 of pregnancy through birth and the level of nerve growth factor (NGF) in the hippocampus and frontal cortex of their male offspring was measured at 20 and 90 days of age. Prenatal choline supplementation caused significant increases in hippocampal NGF levels at 20 and 90 days of age, while levels of NGF in the frontal cortex were elevated in choline-supplemented rats at 20 days of age, but not 90 days of age. These results suggest that increases in NGF levels during development or adulthood may be one mechanism underlying improvements in spatial and temporal memory of adult rats exposed to elevated levels of choline chloride perinatally.
Asunto(s)
Colina/farmacología , Hipocampo/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Nootrópicos/farmacología , Corteza Prefrontal/metabolismo , Efectos Tardíos de la Exposición Prenatal , Envejecimiento/metabolismo , Animales , Tamaño de la Célula/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Femenino , Hipocampo/citología , Hipocampo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Corteza Prefrontal/citología , Corteza Prefrontal/efectos de los fármacos , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Neuropsychiatric disturbances are extremely common in Alzheimer's disease (AD), and represent integral features of the illness, as well as appropriate targets for therapy. We are interested in designing trials aimed at preventing or delaying the emergence of psychopathology in AD. For symptomatic treatment of agitation, mood stabilizers, particularly sodium valproate, have proved to be beneficial in some patients. Since these effects take several weeks to emerge, we considered that they might be dependent on potentially neuroprotective actions of valproate, such as inhibition of apoptosis and slowing of neurofibrillary tangle formation. In this article we present the rationale for testing the neuroprotective potential of valproate experimentally in mouse models of tauopathy and in a clinical trial of patients with AD who lack psychopathology at baseline. Together, these studies will provide important tests of the hypothesis that valproate, either through inhibition of tau phosphorylation or some other mechanism, is a useful therapeutic agent to modify disease progression in AD.