The effect of selegiline in the treatment of people with Alzheimer's disease: a meta‐analysis of published trials

Wilcock, Gordon; Birks, Jacqueline; Whitehead, Anne; Evans, Sir John Grimley

doi:10.1002/gps.545

Cited by 56 publications

(28 citation statements)

References 33 publications

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“…An example of this was illustrated by Jones et al using an IPD meta‐analysis of longitudinal data from five trials that investigated Selegiline versus placebo for the treatment of Alzheimer's disease 84, 86. The outcome of interest over time was the mini‐mental state examination, which is a measure of cognitive function.…”

Section: Key Reasons Why Meta‐analysis Results May Differ For the Onementioning

confidence: 99%

Meta-analysis using individual participant data: one-stage and two-stage approaches, and why they may differ

2016

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Meta‐analysis using individual participant data (IPD) obtains and synthesises the raw, participant‐level data from a set of relevant studies. The IPD approach is becoming an increasingly popular tool as an alternative to traditional aggregate data meta‐analysis, especially as it avoids reliance on published results and provides an opportunity to investigate individual‐level interactions, such as treatment‐effect modifiers. There are two statistical approaches for conducting an IPD meta‐analysis: one‐stage and two‐stage. The one‐stage approach analyses the IPD from all studies simultaneously, for example, in a hierarchical regression model with random effects. The two‐stage approach derives aggregate data (such as effect estimates) in each study separately and then combines these in a traditional meta‐analysis model. There have been numerous comparisons of the one‐stage and two‐stage approaches via theoretical consideration, simulation and empirical examples, yet there remains confusion regarding when each approach should be adopted, and indeed why they may differ.In this tutorial paper, we outline the key statistical methods for one‐stage and two‐stage IPD meta‐analyses, and provide 10 key reasons why they may produce different summary results. We explain that most differences arise because of different modelling assumptions, rather than the choice of one‐stage or two‐stage itself. We illustrate the concepts with recently published IPD meta‐analyses, summarise key statistical software and provide recommendations for future IPD meta‐analyses. © 2016 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.

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Section: Key Reasons Why Meta‐analysis Results May Differ For the Onementioning

confidence: 99%

Meta-analysis using individual participant data: one-stage and two-stage approaches, and why they may differ

2016

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“…An increasing number of molecular biology and pharmacology studies have shown the neuroprotective effects of MAO inhibitors on the prevention and treatment of AD (21,52,53) (Table I) (15,56,57,61,62,112,114,(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144). The main neuroprotective mechanisms of MAO inhibitors in AD include the following: i) Improvement of cognitive impairment (50,54,55), where MAO inhibitors correct chemical imbalances in the brain; ii) antioxidant activities and enhancement of iron-chelating activities (56)(57)(58)(59), where chelators can modulate Aβ accumulation, protect against tau hyperphosphorylation and block metal-associated oxidative stress, thereby holding considerable promise as effective anti-AD drugs (145,146); iii) regulation of APP and Aβ expression processing (56,60), for example ladostigil (TV3326), a selective MAO-B inhibitor, which regulates APP translation and processing (114); iv) the selective MAO inhibitors selegiline and rasagiline have been proven to possess neuroprotective activities in cell cultures and animal models of neurodegenerative diseases through the activation of certain signaling pathways, including p42/44 MAPK and PKC (61); v) inhibition of ChE activity by the MAO inhibitor rasagiline (62)(63)…”

Section: Evidence For the Neuroprotective Effect Of Mao Inhibitors In Admentioning

confidence: 99%

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

Cai

2014

Molecular Medicine Reports

165

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Abstract. Activated monoamine oxidase (MAO) has a critical role in the pathogenesis of Alzheimer's disease (AD), including the formation of amyloid plaques from amyloid β peptide (Aβ) production and accumulation, formation of neurofibrillary tangles, and cognitive impairment via the destruction of cholinergic neurons and disorder of the cholinergic system. Several studies have indicated that MAO inhibitors improve cognitive deficits and reverse Aβ pathology by modulating proteolytic cleavage of amyloid precursor protein and decreasing Aβ protein fragments. Thus, MAO inhibitors may be considered as promising therapeutic agents for AD.

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“…Loss of neurons in the locus coeruleus seems to be a characteristic of AD that correlates with the severity of the dementia (Bondareff et al, 1982) and has not been reported in dementia caused by multiple infarcts (Mann et al, 1982). Deprenyl has been reported to briefly improve cognition in a clinical AD trial (Wilcock et al, 2002). Indeed, the combination of L-deprenyl and physostigmine, an AChE inhibitor, has been shown to be more beneficial in patients with AD than physostigmine alone (Schneider et al, 1993).…”

Section: Galantamine Enhances Nicotine-induced Norepinephrine Releasementioning

confidence: 99%

Effects of Galantamine, a Nicotinic Allosteric Potentiating Ligand, on Nicotine-Induced Catecholamine Release in Hippocampus and Nucleus Accumbens of Rats

Sharp

Yatsula

2004

J Pharmacol Exp Ther

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Galantamine, a drug for treatment of Alzheimer's disease, is a novel cholinergic agent with a dual mode of action that inhibits acetylcholinesterase and allosterically modulates nicotinic cholinergic receptors (nAChRs). Nicotine stimulates catecholamine secretion, inducing hippocampal norepinephrine (NE) release, and improves memory consolidation. Thus, the effect of galantamine on nicotine-induced hippocampal NE secretion was investigated. This was compared with the effect of galantamine on nicotine-induced dopamine (DA) release within the nucleus accumbens of the same rat. Nicotine (0.025-0.09 mg/kg i.v.) dose dependently increased NE and DA levels in microdialysates from the hippocampus and nucleus accumbens, respectively, of freely moving rats. Pretreatment with galantamine (3.0 mg/kg s.c.) 3 h before nicotine either potentiated NE responses to doses of nicotine that were ineffective alone (0.025-0.045 mg/kg) or significantly enhanced (0.065 mg/kg) NE responses, whereas galantamine was ineffective when administered 2 or 4 h before nicotine. In contrast to its effects on NE, galantamine did not alter accumbal DA responses to any dose of nicotine. These selective effects of galantamine on nicotine-stimulated NE secretion may reflect differences in local neural circuits that use nAChRs to modulate hippocampal NE versus accumbal DA release.

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The effect of selegiline in the treatment of people with Alzheimer's disease: a meta‐analysis of published trials

Abstract: Although there was some evidence of improvement with selegiline in the short term in cognition and activities of daily living, the magnitude of the effect did not reach clinical importance. There was no evidence of long term effects.

Cited by 56 publications

References 33 publications

Meta-analysis using individual participant data: one-stage and two-stage approaches, and why they may differ

Meta-analysis using individual participant data: one-stage and two-stage approaches, and why they may differ

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

Effects of Galantamine, a Nicotinic Allosteric Potentiating Ligand, on Nicotine-Induced Catecholamine Release in Hippocampus and Nucleus Accumbens of Rats

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