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

作　　者：Burak Yulug Ozlem Altay Xiangyu Li Lutfu Hanoglu Seyda Cankaya Simon Lam Halil Aziz Velioglu Hong Yang Ebru Coskun Ezgi Idil Rahim Nogaylar Ahmet Ozsimsek Cemil Bayram Ismail Bolat Sena Oner Ozlem Ozdemir Tozlu Mehmet Enes Arslan Ahmet Hacimuftuoglu Serkan Yildirim Muhammad Arif Saeed Shoaie Cheng Zhang Jens Nielsen Hasan Turkez Jan Borén Mathias Uhlén Adil Mardinoglu 

机构地区：[1]Department of Neurology and Neuroscience,Faculty of Medicine,Alanya Alaaddin Keykubat University,Antalya,Turkey [2]Science for Life Laboratory,KTH-Royal Institute of Technology,Stockholm,Sweden [3]Department of Neurology,Faculty of Medicine,Istanbul Medipol University,Istanbul,Turkey [4]Centre for Host-Microbiome Interaction’s,Faculty of Dentistry,Oral and Craniofacial Sciences,King’s College London,London,UK [5]Department of Women’s and Children’s Health,Karolinska Institute,Stockholm,Sweden [6]Functional Imaging and Cognitive-Affective Neuroscience Lab,Istanbul Medipol Univer-sity,Istanbul,Turkey [7]Department of Medical Pharmacology,Faculty of Medi-cine,Atatürk University,Erzurum,Turkey [8]Department of Pathology,Veterinary Faculty,Ataturk University,Erzurum,Turkey [9]Department of Molecular Biology and Genetics,Faculty of Science,Erzurum Technical University,Erzurum,Tur-key [10]School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou,People’s Republic of China [11]Department of Biology and Biological Engineering,Chalmers University of Technology,Gothenburg,Sweden [12]Department of Medical Biology,Faculty of Medicine,Atatürk University,Erzurum,Turkey [13]Department of Molecular and Clinical Medicine,University of Gothenburg and Sahlgrenska University Hospital,Gothenburg,Sweden.

出　　处：《Translational Neurodegeneration》2023年第1期849-871,共23页转化神经变性病（英文）

基　　金：funding provided by Royal Institute of Technology.This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation(72110).

摘　　要：Background 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

关 键 词：Alzheimer’s disease Combined metabolic activators Multi-omics Systems biology Systems medicine 

分 类 号：R749.16[医药卫生—神经病学与精神病学]