Memantine enhances autonomy in moderate to severe Alzheimer's disease

Rive, B.; Vercelletto, Martine; Damier, F. Delamarre; Cochran, John M; François, Clément

doi:10.1002/gps.1112

Cited by 33 publications

(24 citation statements)

References 18 publications

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“…The microglial-mediated death mechanism we observed may provide specific molecular targets amenable to targeting for neuroprotective therapeutic design. For example, the success of the noncompetitive NMDA receptor antagonist, memantine, for treatment of AD patients supports the idea that NMDA receptor activity is required for disease progression (Jain, 2000;Marx, 2000;Reisberg et al, 2003;Rive et al, 2004;Tariot et al, 2004). Finally, it is conceivable that the inflammationassociated death we characterized may be mechanistically important for neuron loss in a variety of inflammation-associated neurodegenerative conditions besides AD.…”

Section: Discussionmentioning

confidence: 60%

“…It is known that NMDA receptor (NMDAR)-expressing neurons are vulnerable to AD-associated loss, supporting a hypothesis of excitotoxic NMDA receptor activity-mediated death (Greenamyre and Young, 1989;Francis et al, 1993). Encouraging clinical trial data from Alzheimer's patients treated with the noncompetitive NMDA receptor antagonist memantine also supports the idea that NMDA receptor activity is required for disease progression (Jain, 2000;Marx, 2000;Reisberg et al, 2003;Rive et al, 2004;Tariot et al, 2004). Although the effectors of neuron loss remain unclear, data suggest that death may include oxidative damageassociated mechanisms as evidenced by increased neuronal immunoreactivity for inducible nitric oxide synthase (iNOS) and the peroxynitrite marker 3-nitrotyrosine (Vodovotz et al, 1996;Smith et al, 1997;Hensley et al, 1998;Heneka et al, 2001).…”

Section: Introductionmentioning

confidence: 89%

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β-Amyloid-Stimulated Microglia Induce Neuron Death via Synergistic Stimulation of Tumor Necrosis Factor α and NMDA Receptors

Floden¹,

Li²,

Combs³

2005

J. Neurosci.

224

158

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Although abundant reactive microglia are found associated with ␤-amyloid (A␤) plaques in Alzheimer's disease (AD) brains, their contribution to cell loss remains speculative. A variety of studies have documented the ability of A␤ fibrils to directly stimulate microglia in vitro to assume a neurotoxic phenotype characterized by secretion of a plethora of proinflammatory molecules. Collectively, these data suggest that activated microglia play a direct role in contributing to neuron death in AD rather than simply a role in clearance after plaque deposition. Although it is clear the A␤-stimulated microglia acutely secrete toxic oxidizing species, the identity of longer-lived neurotoxic agents remains less defined. We used A␤-stimulated conditioned media from primary mouse microglia to identify more stable neurotoxic secretions. The NMDA receptor antagonists memantine and 2-amino-5-phosphopetanoic acid as well as soluble tumor necrosis factor ␣ (TNF␣) receptor protect neurons from microglial-conditioned media-dependent death, implicating the excitatory neurotransmitter glutamate and the proinflammatory cytokine TNF␣ as effectors of microglial-stimulated death. Neuron death occurs in an oxidative damage-dependent manner, requiring activity of inducible nitric oxide synthase. Toxicity results from coincident stimulation of the TNF␣ and NMDA receptors, because stimulations of either alone are insufficient to initiate cell death. These findings suggest the hypothesis that AD brains provide the appropriate microglial-mediated inflammatory environment for TNF␣ and glutamate to synergistically stimulate toxic activation of their respective signaling pathways in neurons as a contributing mechanism of cell death.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 89%

β-Amyloid-Stimulated Microglia Induce Neuron Death via Synergistic Stimulation of Tumor Necrosis Factor α and NMDA Receptors

Floden¹,

Li²,

Combs³

2005

J. Neurosci.

224

158

View full text Add to dashboard Cite

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“…To analyze how interpretation is subject to the influence of disease severity and instruments used, we reanalyzed two clinical studies with memantine in patients with AD using more than one scale targeting the same endpoint ‘cognition’. Despite several clinical studies demonstrating the efficacy of memantine in patients with AD in a variety of settings [5,19,20,25,26] several meta-analyses considered the therapeutic efficacy on ‘cognition’ to be small [1,14]. The analysis in the current manuscript demonstrates that rather than only performing meta-analyses over the whole spectrum of disease severity and clinical scales, an itemized analysis with regard to severity of disease and instrument used is also necessary.…”

Section: Discussionmentioning

confidence: 99%

Measuring Therapeutic Efficacy in Patients with Alzheimer’s Disease: Role of Instruments

Riepe

Janetzky²,

Lemming³

2011

Dement Geriatr Cogn Disord

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Background/Aims: Global cognitive scales and meta-analyses thereof are used to appraise therapeutic efficacy over a broad range of disease severity. Clinically, however, different aspects of cognition change in different stages of disease. Methods: Calculation of effect sizes for single cognitive functions on treatment as assessed by the Alzheimer’s Disease Assessment Scale (ADAS-cog), the Mini-Mental-Status Examination (MMSE), and the Severe Impairment Battery (SIB). In these scales, subdomains of ‘cognition’, e.g. memory and language, are represented in different proportions. To exemplify the analysis of ‘cognition’, we used original data of previously published clinical studies with memantine. Results: Depending on dementia severity and on the scale used, the effect size for memory varies between –0.44 and +0.34 and for language between –0.40 and +0.26. Conclusion: Beyond interstudy variance, effect sizes for treatment with antidementia drugs are subject to disease stage, instruments used, and interaction thereof. Therefore, clinical interpretation is necessary to appraise therapeutic efficacy in clinical studies and meta-analyses thereof when patients with different severity are included or different instruments are used. Alternatively, severity-adapted endpoints should be used for appraisal and meta-analysis of therapeutic efficacy.

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“…Subsequently, patients were classified as either dependent or independent according to the method developed by Rive et al [19]. This study demonstrated that the dependency status of AD patients after 6 months was influenced by initial dependency status, memantine treatment and initial severity.…”

Section: Model Structurementioning

confidence: 98%

“…Caregiver stress is related to the patients' behavioural symptoms and impairments in the activities of daily living [17]. Moreover, the level of patient dependency is directly related to the amount of time caregivers spend [18,19]. The more dependent the patients are, the more time is required for assisting them in everyday life.…”

Section: Introductionmentioning

confidence: 99%

Cost-effectiveness of memantine in community-based Alzheimer’s disease patients: an adaptation in Spain

Antoñanzas¹,

Rive

Badenas

et al. 2006

Eur J Health Econ

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Several clinical trials have demonstrated the efficacy and safety of the NMDA antagonist memantine in moderately severe to severe Alzheimer's disease (AD) patients. A 28-week pharmacoeconomic study conducted in the US also showed a reduction of total healthcare costs and informal care compared to placebo. Long-term implications of memantine treatment were modelled in the UK and Finland and revealed reductions in dependency, institutionalization and costs. However, these conclusions were not directly applicable to the Spanish setting where patients are mainly treated within the community. The objective of this study was to estimate the long-term implications in terms of costs and health benefits of memantine therapy compared to standard care using a Spanish adaptation of previous models over a 2-year time horizon. As in previous adaptations, Markov health states were defined as a combination of severity (mild-moderate, moderately severe, severe) and dependency plus death as the absorbing state. Spain-specific data (costs, mortality and epidemiological data) were obtained from local and recently published cohorts of AD patients. Data on the effectiveness of memantine were derived from a randomized double-blind placebo-controlled clinical trial of 252 moderately severe to severe AD patients. Effectiveness was measured as the time spent in a non-dependent health state. The evaluation was conducted over 2 years, while the efficacy of memantine was applied for 1 year only in order to ensure a conservative approach. The robustness of the model was tested by conducting stochastic analyses and various sensitivity analyses on the key assumptions. Patients receiving standard care were estimated to spend 6 months in a non-dependent state and to incur average total costs of Euro 24,700 over 2 years. The memantine strategy was associated with an additional 2.5 months in a non-dependent state and a Euro 700 cost reduction. Monte-Carlo simulations and sensitivity analyses supported these findings. Memantine appears to be cost-effective compared with standard care in moderately severe to severe AD patients in a Spanish setting. The prolonged independence provided by memantine treatment translated into cost reductions which offset drug costs and resulted in overall cost-savings.

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Memantine enhances autonomy in moderate to severe Alzheimer's disease

Abstract: Memantine enhances autonomy in patients with moderately-severe to severe AD by increasing the probability of their remaining autonomous, therefore delaying transition to the dependent stage.

Cited by 33 publications

References 18 publications

β-Amyloid-Stimulated Microglia Induce Neuron Death via Synergistic Stimulation of Tumor Necrosis Factor α and NMDA Receptors

β-Amyloid-Stimulated Microglia Induce Neuron Death via Synergistic Stimulation of Tumor Necrosis Factor α and NMDA Receptors

Measuring Therapeutic Efficacy in Patients with Alzheimer’s Disease: Role of Instruments

Cost-effectiveness of memantine in community-based Alzheimer’s disease patients: an adaptation in Spain

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