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Öğe Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial(2023) Yuluğ, Burak; Altay, Özlem; Li, Xiangyu; Hanoğlu, Lütfü; Çankaya, Şeyda; Lam, Simon; Velioğlu, Halil Aziz; Yang, Hong; Coşkun, Ebru; İdil, Ezgi; Nogaylar, Rahim; Özşimşek, Ahmet; Bayram, Cemil; Bolat, İsmail; Öner, Sena; Tozlu, Özlem Özdemir; Arslan, Mehmet Enes; Hacımüftüoğlu, Ahmet; Yıldırım, Serkan; Arif, Muhammad; Shoaie, Saeed; Zhang, Cheng; Nielsen, Jens; Turkez, Hasan; Boren, Jan; Uhlen, Mathias; Mardinoğlu, AdilAbstract 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 efect 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 frst 28 days and twice daily between day 28 and day 84. The primary endpoint was the diference 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 efcacy of the CMA in AD patients. Results We showed a signifcant 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 signifcant 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 ofÖğe Multi-omics analysis reveals the key factors involved in the severity of the Alzheimer's disease(Bmc, 2024) Meng, Lingqi; Jin, Han; Yulug, Burak; Altay, Ozlem; Li, Xiangyu; Hanoglu, Lutfu; Cankaya, SeydaAlzheimer's disease (AD) is a debilitating neurodegenerative disorder with a global impact, yet its pathogenesis remains poorly understood. While age, metabolic abnormalities, and accumulation of neurotoxic substances are potential risk factors for AD, their effects are confounded by other factors. To address this challenge, we first utilized multi-omics data from 87 well phenotyped AD patients and generated plasma proteomics and metabolomics data, as well as gut and saliva metagenomics data to investigate the molecular-level alterations accounting the host-microbiome interactions. Second, we analyzed individual omics data and identified the key parameters involved in the severity of the dementia in AD patients. Next, we employed Artificial Intelligence (AI) based models to predict AD severity based on the significantly altered features identified in each omics analysis. Based on our integrative analysis, we found the clinical relevance of plasma proteins, including SKAP1 and NEFL, plasma metabolites including homovanillate and glutamate, and Paraprevotella clara in gut microbiome in predicting the AD severity. Finally, we validated the predictive power of our AI based models by generating additional multi-omics data from the same group of AD patients by following up for 3 months. Hence, we observed that these results may have important implications for the development of potential diagnostic and therapeutic approaches for AD patients.Öğe Multi-omics characterization of improved cognitive functions in Parkinson's disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial(Oxford Univ Press, 2025) Yulug, Burak; Altay, Ozlem; Li, Xiangyu; Hanoglu, Lutfu; Cankaya, Seyda; Velioglu, Halil A.; Lam, SimonParkinson's disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson's disease and Alzheimer's disease animal models and the cognitive functions in Alzheimer's disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson's disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson's Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson's disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson's disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson's disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson's disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson's disease patients as recently shown in Alzheimer's disease patients. The trial was registered in ClinicalTrials.gov NCT04044131 (17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131).Öğe Retraction notice to “Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases” [Life Sci. 314 (2023) 121325] (Life Sciences (2023) 314, (S0024320522010256), (10.1016/j.lfs.2022.121325))(Elsevier Inc., 2024) Türkez, Hasan; Altay, Ozlem; Yildirim, Serkan; Li, Xiangyu; Yang, Hong; Bayram, Cemil; Bolat, İsmailThis article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of Editor-in-Chief. The journal was alerted to concerns about the validity of the images shown in Figs. 3, 6 and 7 as also detailed in the following Pubpeer post: https://pubpeer.com/publications/BDEA6585A4941F7F97EB34426937FF. As per the journal policy, the authors were contacted on this matter, and they informed the journal that wrong images were included in the above-mentioned figures by accident. The authors claimed that the unintentional inclusion of the wrong images worsened the results and asked for a corrigendum in April 2023. The authors also offered to submit the raw data and physical pathology slides to be analysed by independent experts. The Editor has declined the authors' offer and decided to retract the article due to these concerns. The authors do not agree with the retraction and have maintained that the retraction of their article is not in line with Elsevier policy. They have included their explanation of the issues in the comments section of the Pubpeer post. © 2024 The Author(s)
