Diagnosis and treatment of Alzheimer’s disease

Desai, Abhilash K.; Grossberg, George T.

doi:10.1212/wnl.64.12_suppl_3.s34

Cited by 130 publications

(63 citation statements)

References 60 publications

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“…The cause of AD is not yet clear. Pathological studies revealed the existence of neuritic plaques in the brains of AD patients (Desai and Grossberg, 2005;Blennow et al, 2006). The plaques are mainly composed of amyloid-␤ (A␤) peptides that are formed by the sequential cleavage of the amyloid precursor protein (APP).…”

Section: Introductionmentioning

confidence: 99%

Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

Yi¹,

Hadden²,

Kulanthaivel³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Semagacestat is a functional ␥-secretase inhibitor that has been shown to reduce the rate of formation of amyloid-␤ in vitro and in vivo. This study was conducted to characterize the disposition of semagacestat in humans. After a single 140-mg dose of [ 14 C]semagacestat administered as an oral solution to six healthy male subjects, semagacestat was rapidly absorbed (T max ϳ0.5 h) and eliminated from the systemic circulation (terminal t 1/2 ϳ2.4 h). The major circulating metabolites of semagacestat, M2 (hydrolysis of the amide bond proximal to the benzazepine ring) and M3 (benzylic hydroxylation of the benzazepine ring), accounted for approximately 27 and 10% of total radioactivity exposure, respectively, as calculated from relative area under the plasma concentration versus time curve from 0 to 24 h derived from the plasma radiochro- Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by cognitive impairment. The prevalence rate is approximately 6% among those aged more than 65 years. Currently more than 4 million Americans suffer from AD, and this number is expected to quadruple by year 2050 as average lifespan increases (Rice et al., 2001;Joyce et al., 2007). AD has a substantial impact on patients, caregivers, and the healthcare system. Average total medical costs for AD patients are more than 5-fold higher than those for control populations. Development of pharmaceuticals for the treatment of AD would greatly benefit AD patients and society. The cause of AD is not yet clear. Pathological studies revealed the existence of neuritic plaques in the brains of AD patients (Desai and Grossberg, 2005;Blennow et al., 2006). The plaques are mainly composed of amyloid-␤ (A␤) peptides that are formed by the sequential cleavage of the amyloid precursor protein (APP). APP is first cleaved by the ␤-site APP-cleaving enzyme to form the N terminus of A␤, which is further cleaved by ␥-secretase at multiple sites to form A␤ isoforms ranging from 37 (A␤37) to 43 (A␤43) residues (Olson and Albright, 2008). Mutations in APP near cleavage sites resulting in the A␤ formation have been linked to AD in several families (Selkoe, 2001;Imbimbo, 2008). This observation suggests that a reduction in A␤ synthesis could slow the disease progression in patients with AD.Semagacestat, an azepine class ␥-secretase inhibitor, is one of a very few ␥-secretase inhibitors that have been advanced into clinical trials as potential disease-modifying agents for the treatment of AD (Olson and Albright, 2008). Semagacestat reduces the rate of formation of A␤ in whole cell assays, as well as in transgenic and nontransgenic mice, beagle dogs, and guinea pigs Hyslop et al., 2004;May et al., 2004;Lanz et al., 2006). A transgenic mouse model of AD was generated using a platelet-derived growth factor ␤ promoter driving a human APP minigene encoding the APP V171F mutation (PDAPP mouse). These mice express high levels of human mutant APP and progressively develop many of the pathologArticle, publication date, and citation ...

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Section: Introductionmentioning

confidence: 99%

Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

Yi¹,

Hadden²,

Kulanthaivel³

et al. 2010

Drug Metab Dispos

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“…They must display high sensitivity and specificity, while ease-of use is also an important factor to be defined as biomarkers. (Desai and Grossberg, 2005; (Alzheimer's, 2015, Hebert et al, 2013, Thies et al, 2013. Humpel, 2011).…”

Section: Current Markers Of Admentioning

confidence: 99%

Small molecule biomarkers in Alzheimer’s disease

Kim

Legido‐Quigley

2018

OCL

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-Alzheimer's disease (AD) is a progressive neurodegenerative disease which affects a growing number of people as the population ages worldwide. Alzheimer's Disease International estimated that more than 100 million people will be living with dementia by 2050. At present there are no disease-modifying therapies and research has expanded to the Àomic sciences with scientists aiming to get a holistic view of the disease using systems medicine. Metabolomics and Lipidomics give a snap-shot of the metabolism. As analyzing the brain in vivo is difficult, the metabolic information of the periphery has potential to unravel mechanisms that have not been considered, such as those that link the brain to the liver and the gut or other organs. With that in mind we have produced a mini-review, to record a number of studies in the field and the molecular pathways that have been flagged in animal and human models of AD. Human studies deal with cohorts in the order of the hundreds due to the difficulty of organizing AD studies, however it is possible that these first pilots point towards important mechanisms. The trend in these small studies is the involvement of many organs and pathways. Some findings, that have been reproduced, are ceramides being increased, phospholipids and neurotransmitters depleted and sterols being found depleted too. Initial findings point to an important role to lipid homeostasis in AD, this is not surprising as the brain's main constituents are water and lipids.Keywords: Alzheimer's disease / metabolomics / lipidomics / biomarker Résumé -Biomarqueurs à petites molécules dans la maladie d'Alzheimer. La maladie d'Alzheimer est une maladie neurodégénérative progressive qui affecte un nombre croissant de personnes en raison du vieillissement de la population observé dans le monde entier. La fédération internationale d'associations Alzheimer's disease International estime que plus de 100 millions de personnes vivront avec cette démence d'ici à 2050. Il n'existe actuellement aucun traitement de la maladie et la recherche s'est élargie aux sciences -omiques avec l'objectif scientifique d'obtenir une approche globale de la maladie en utilisant une médecine des systèmes. La métabolomique et la lipidomique donnent un aperçu du métabolisme. L'analyse du cerveau in vivo s'avérant difficile, l'information métabolique de la périphérie possède le potentiel de démêler des mécanismes qui n'ont pas été pris en compte, tels que ceux reliant le cerveau au foie et à l'intestin ou à d'autres organes. Dans cet esprit, nous proposons une mini-revue, afin de lister un certain nombre d'études relevant de ce champ et les voies moléculaires qui ont été signalées chez les modèles animaux et humains de la maladie d'Alzheimer. Les études humaines traitent des cohortes de quelque centaines d'individus en raison de la difficulté à organiser des études sur cette pathologie, mais il est possible que ces premiers pilotes pointent vers des mécanismes importants. La tendance dans ces petites études est l'implication de nombreux org...

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“…4,5 The prevalence of dementia due to AD increases with age, such that AD accounts for 5% of dementia cases in the age group of 65-74 years and 50% in the age group over 85 years. 6 AD is responsible for reduction of life expectancy by 50% from the time of diagnosis in elderly patients. 7 AD is characterized by destruction of the functional activity of neurons in the cerebral cortex, amygdale, frontal base, limbic system and hippocampus, and also by cortical atrophy, thereby causing impairment of cholinergic synapses in the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

Perspectives for treating Alzheimer's disease: a review on promising pharmacological substances

et al. 2016

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CONTEXT AND OBJECTIVE: Dementia is a syndrome characterized by functional and cognitive decline. Alzheimer's disease (AD) is one of the most common causes of dementia and has high prevalence among the elderly. It is known that there is no drug capable of interfering with the course of the disease. Research on treatments for AD has been marked by the appearance of new drugs and their abandonment. This study aimed to describe drugs that have been studied with regard to treating AD and which are capable of influencing the course of the disease. DESIGN AND SETTING: Narrative review on original articles published worldwide. METHODS: A systematized search was conducted in the PubMed/MEDLINE, Cochrane Library/Cochrane and SciELO/Bireme databases. The descriptors "Molecular Mechanisms of Pharmacological Action" and "Drug Therapy" were each combined with the descriptor "Alzheimer disease". All of these can be found in MeSH and DeCS. These descriptors were used alone or in combination, and a filter specifying publication between January 2009 and October 2015 in English, Spanish or Portuguese was set. RESULTS: 6,888 articles were found, of which 37 were included in this review; 70.3% of the articles selected were of good quality with low or unclear risk of bias. 86 drugs were considered promising for AD treatment and these were classified into 20 pharmacological categories. CONCLUSION: There are no drugs capable of influencing the course of AD such that treatments are safe and effective. However, immunomodulators stood out as promising, given their effectiveness and quality in the articles analyzed. RESUMO CONTEXTO E OBJETIVO:A demência é uma síndrome caracterizada por declínio funcional e cognitivo, sendo a doença de Alzheimer (DA) uma das causas mais comuns e de alta prevalência em idosos. Sabe-se que não há medicamento capaz de interferir no curso da doença e as pesquisas para o tratamento da DA têm sido marcadas pelo surgimento e abandono de novas drogas. O objetivo deste estudo foi descrever as drogas capazes de influenciar o curso da DA que têm sido estudadas para o tratamento da doença.

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Diagnosis and treatment of Alzheimer’s disease

Cited by 130 publications

References 60 publications

Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

Small molecule biomarkers in Alzheimer’s disease

Perspectives for treating Alzheimer's disease: a review on promising pharmacological substances

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