Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: A randomised, double-blinded, placebo-controlled phase-II trial

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dc.authorid0000-0003-4292-5717
dc.authorid0000-0002-2306-5937
dc.authorid0000-0003-1028-6703
dc.contributor.authorYuluğ, Burak
dc.contributor.authorAltay, Özlem
dc.contributor.authorLi, Xiangyu
dc.contributor.authorHanoğlu, Lütfü
dc.contributor.authorÇankaya, Şeyda
dc.contributor.authorLam, Simon
dc.contributor.authorVelioğlu, Halil Aziz
dc.contributor.authorYang, Hong
dc.contributor.authorCoşkun, Ebru
dc.contributor.authorİdil, Ezgi
dc.contributor.authorNogaylar, Rahim
dc.contributor.authorÖzşimşek, Ahmet
dc.contributor.authorBayram, Cemil
dc.contributor.authorBolat, İsmail
dc.contributor.authorÖner, Sena
dc.contributor.authorÖzdemir Tozlu, Özlem
dc.contributor.authorArslan, Mehmet Enes
dc.contributor.authorHacimuftüoğlu, Ahmet
dc.contributor.authorYıldırım, Serkan
dc.contributor.authorArif, Muhammad
dc.contributor.authorShoaie, Saeed
dc.contributor.authorZhang, Cheng
dc.contributor.authorNielsen, Jens
dc.contributor.authorTürkez, Hasan
dc.contributor.authorBorén, Jan
dc.contributor.authorUhlén, Mathias
dc.contributor.authorMardinoglu, Adil
dc.date.accessioned2023-02-10T11:40:17Z
dc.date.available2023-02-10T11:40:17Z
dc.date.issued2023
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Nöroloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.description.abstractBackground: Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Methods: Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. Results: We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Conclusion: Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131.
dc.identifier.citationYuluğ, B., Altay, Ö., Li, X., Hanoğlu, L., Çankaya, Ş., Lam, S. ... Mardinoglu, A. (2023). Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: A randomised, double-blinded, placebo-controlled phase-II trial. Translational Neurodegeneration, 12(1). https://dx.doi.org/10.1186/s40035-023-00336-2
dc.identifier.doi10.1186/s40035-023-00336-2
dc.identifier.issn2047-9158
dc.identifier.issue1
dc.identifier.pmid36703196
dc.identifier.scopus2-s2.0-85146871450
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://dx.doi.org/10.1186/s40035-023-00336-2
dc.identifier.urihttps://hdl.handle.net/20.500.12511/10418
dc.identifier.volume12
dc.identifier.wos000922978700001en_US
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorHanoğlu, Lütfü
dc.institutionauthorVelioğlu, Halil Aziz
dc.institutionauthorCoşkun, Ebru
dc.language.isoen
dc.publisherBioMed Central Ltd
dc.relation.ispartofTranslational Neurodegenerationen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsAttribution 4.0 International*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subjectAlzheimer’s Disease
dc.subjectCombined Metabolic Activators
dc.subjectMulti-omics
dc.subjectSystems Biology
dc.subjectSystems Medicine
dc.titleCombined metabolic activators improve cognitive functions in Alzheimer's disease patients: A randomised, double-blinded, placebo-controlled phase-II trial
dc.typeArticle

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