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

Burak Yulug; Ozlem Altay; Xiangyu Li; Lutfu Hanoglu; Seyda Cankaya; Halil A. Velioglu; Simon Lam; Hong Yang; Ebru Coskun; Ezgi Idil; Zubeyir Bayraktaroglu; Rahim Nogaylar; Ahmet Ozsimsek; Serkan Yildirim; Ismail Bolat; Metin Kiliclioglu; Cemil Bayram; Nursena Yuksel; Ozlem O. Tozlu; Muhammad Arif; Saeed Shoaie; Ahmet Hacimuftuoglu; Cheng Zhang; Jens Nielsen; Hasan Turkez; Jan Borén; Mathias Uhlén; Adil Mardinoglu

doi:10.1093/braincomms/fcae478

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

Burak Yulug, Ozlem Altay, Xiangyu Li, Lutfu Hanoglu, Seyda Cankaya, Halil A. Velioglu, Simon Lam, Hong Yang, Ebru Coskun, Ezgi Idil, Zubeyir Bayraktaroglu, Rahim Nogaylar, Ahmet Ozsimsek, Serkan Yildirim, Ismail Bolat, Metin Kiliclioglu, Cemil Bayram, Nursena Yuksel, Ozlem O. Tozlu, Muhammad ArifSaeed Shoaie, Ahmet Hacimuftuoglu, Cheng Zhang, Jens Nielsen, Hasan Turkez, Jan Borén, Mathias Uhlén, Adil Mardinoglu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Parkinson’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.

Original language	English
Article number	fcae478
Journal	Brain Communications
Volume	7
Issue number	1
DOIs	https://doi.org/10.1093/braincomms/fcae478
Publication status	Published - 2025

Keywords

combined metabolic activators
multi-omics
Parkinson’s disease
systems biology

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Yulug, B., Altay, O., Li, X., Hanoglu, L., Cankaya, S., Velioglu, H. A., Lam, S., Yang, H., Coskun, E., Idil, E., Bayraktaroglu, Z., Nogaylar, R., Ozsimsek, A., Yildirim, S., Bolat, I., Kiliclioglu, M., Bayram, C., Yuksel, N., Tozlu, O. O., ... Mardinoglu, A. (2025). 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. Brain Communications, 7(1), Article fcae478. https://doi.org/10.1093/braincomms/fcae478

@article{dbf9acbae13245e4b4c25bf8758ca4b2,

title = "Multi-omics characterization of improved cognitive functions in Parkinson{\textquoteright}s disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial",

abstract = "Parkinson{\textquoteright}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{\textquoteright}s disease and Alzheimer{\textquoteright}s disease animal models and the cognitive functions in Alzheimer{\textquoteright}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{\textquoteright}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{\textquoteright}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{\textquoteright}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{\textquoteright}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{\textquoteright}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{\textquoteright}s disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson{\textquoteright}s disease patients as recently shown in Alzheimer{\textquoteright}s disease patients.",

keywords = "combined metabolic activators, multi-omics, Parkinson{\textquoteright}s disease, systems biology",

author = "Burak Yulug and Ozlem Altay and Xiangyu Li and Lutfu Hanoglu and Seyda Cankaya and Velioglu, {Halil A.} and Simon Lam and Hong Yang and Ebru Coskun and Ezgi Idil and Zubeyir Bayraktaroglu and Rahim Nogaylar and Ahmet Ozsimsek and Serkan Yildirim and Ismail Bolat and Metin Kiliclioglu and Cemil Bayram and Nursena Yuksel and Tozlu, {Ozlem O.} and Muhammad Arif and Saeed Shoaie and Ahmet Hacimuftuoglu and Cheng Zhang and Jens Nielsen and Hasan Turkez and Jan Bor{\'e}n and Mathias Uhl{\'e}n and Adil Mardinoglu",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

doi = "10.1093/braincomms/fcae478",

language = "English",

volume = "7",

journal = "Brain Communications",

issn = "2632-1297",

publisher = "Oxford University Press",

number = "1",

}

Yulug, B, Altay, O, Li, X, Hanoglu, L, Cankaya, S, Velioglu, HA, Lam, S, Yang, H, Coskun, E, Idil, E, Bayraktaroglu, Z, Nogaylar, R, Ozsimsek, A, Yildirim, S, Bolat, I, Kiliclioglu, M, Bayram, C, Yuksel, N, Tozlu, OO, Arif, M, Shoaie, S, Hacimuftuoglu, A, Zhang, C, Nielsen, J, Turkez, H, Borén, J, Uhlén, M & Mardinoglu, A 2025, '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', Brain Communications, vol. 7, no. 1, fcae478. https://doi.org/10.1093/braincomms/fcae478

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. / Yulug, Burak; Altay, Ozlem; Li, Xiangyu et al.
In: Brain Communications, Vol. 7, No. 1, fcae478, 2025.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Multi-omics characterization of improved cognitive functions in Parkinson’s disease patients after the combined metabolic activator treatment

T2 - a randomized, double-blinded, placebo-controlled phase II trial

AU - Yulug, Burak

AU - Altay, Ozlem

AU - Li, Xiangyu

AU - Hanoglu, Lutfu

AU - Cankaya, Seyda

AU - Velioglu, Halil A.

AU - Lam, Simon

AU - Yang, Hong

AU - Coskun, Ebru

AU - Idil, Ezgi

AU - Bayraktaroglu, Zubeyir

AU - Nogaylar, Rahim

AU - Ozsimsek, Ahmet

AU - Yildirim, Serkan

AU - Bolat, Ismail

AU - Kiliclioglu, Metin

AU - Bayram, Cemil

AU - Yuksel, Nursena

AU - Tozlu, Ozlem O.

AU - Arif, Muhammad

AU - Shoaie, Saeed

AU - Hacimuftuoglu, Ahmet

AU - Zhang, Cheng

AU - Nielsen, Jens

AU - Turkez, Hasan

AU - Borén, Jan

AU - Uhlén, Mathias

AU - Mardinoglu, Adil

PY - 2025

Y1 - 2025

N2 - Parkinson’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.

AB - Parkinson’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.

KW - combined metabolic activators

KW - multi-omics

KW - Parkinson’s disease

KW - systems biology

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U2 - 10.1093/braincomms/fcae478

DO - 10.1093/braincomms/fcae478

M3 - Article

AN - SCOPUS:85215432829

SN - 2632-1297

VL - 7

JO - Brain Communications

JF - Brain Communications

IS - 1

M1 - fcae478

ER -

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

Abstract

Keywords

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