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

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dc.authorid0000-0002-3721-8586
dc.authorid0000-0003-1028-6703
dc.authorid0000-0002-4476-0971
dc.authorid0000-0002-2306-5937
dc.authorid0000-0001-5834-4533
dc.authorid0000-0002-9704-6173
dc.authorid0000-0001-9055-2164
dc.contributor.authorYulug, Burak
dc.contributor.authorAltay, Ozlem
dc.contributor.authorLi, Xiangyu
dc.contributor.authorHanoglu, Lutfu
dc.contributor.authorCankaya, Seyda
dc.contributor.authorVelioglu, Halil A.
dc.contributor.authorLam, Simon
dc.date.accessioned2026-01-24T12:28:59Z
dc.date.available2026-01-24T12:28:59Z
dc.date.issued2025
dc.departmentAlanya Alaaddin Keykubat Üniversitesi
dc.description.abstractParkinson'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).
dc.description.sponsorshipScandiBio Therapeutics [sllstore2017024]; Swedish National Infrastructure for Computing (SNIC) at UPPMAX [2018-05973]; Swedish Research Council
dc.description.sponsorshipThe authors would like to thank Metabolon Inc. (Durham, USA) for generating the metabolomics data, Olink Proteomics AB (Uppsala, Sweden) for producing the proteomics data and ChromaDex Inc. (Irvine, CA, USA) for supplying the NR. The computations and data processing were supported by resources provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, under Project sllstore2017024, and partially funded by the Swedish Research Council through grant agreement no. 2018-05973.
dc.identifier.doi10.1093/braincomms/fcae478
dc.identifier.issn2632-1297
dc.identifier.issue1
dc.identifier.pmid39816194
dc.identifier.scopus2-s2.0-85215432829
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1093/braincomms/fcae478
dc.identifier.urihttps://hdl.handle.net/20.500.12868/5036
dc.identifier.volume7
dc.identifier.wosWOS:001397642700001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherOxford Univ Press
dc.relation.ispartofBrain Communications
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WoS_20260121
dc.subjectParkinson's disease
dc.subjectcombined metabolic activators
dc.subjectsystems biology
dc.subjectmulti-omics
dc.titleMulti-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
dc.typeArticle

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