Urinary metabolic phenotyping for Alzheimer’s disease

Kurbatova, Natalja; Garg, Manik; Whiley, Luke; Chekmeneva, Elena; Jiménez, Beatriz; Gómez-Romero, María José; Pearce, Jake T M; Kimhofer, Torben; D’Hondt, Ellie; Kłoszewska, Iwona; Mecocci, Patrizia; Tsolaki, Magda; Vellas, Bruno; Aarsland, Dag; Nevado‐Holgado, Alejo J.; Liu, Benjamine; Snowden, Stuart G.; Proitsi, Petroula; Ashton, Nicholas J.; Hye, Abdul; Legido‐Quigley, Cristina; Lewis, Matthew R.; Nicholson, Jeremy K.; Holmes, Elaine; Brāzma, Alvis; Lovestone, Simon

doi:10.1038/s41598-020-78031-9

Cited by 37 publications

(27 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite insufficient clinical AD data concerning cholesterol metabolites and dicarboxylic acids (DCAs), we observed significantly lower levels of these metabolites after CMA treatment 79 . Levels of pregnanediol, a metabolite of pregnenolone, and DCAs, end-products of β -or omega oxidation, which were observed as decreased in the present study, were previously reported to be lower in the urine of patients with AD 80,81 . Considering the neurotoxic role of bile acids, along with the oxidative properties of DCAs, the detection of decreased levels of bile acid metabolites and DCA products in the present study is therefore not surprising.…”

Section: Discussionsupporting

confidence: 74%

Combined Metabolic Activators Improves Cognitive Functions in Alzheimer’s Disease

Yuluğ

Altay

et al. 2021

Preprint

View full text Add to dashboard Cite

Alzheimer's disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. Here, we analyzed the brain transcriptomics data of more than 600 AD patients using genome-scale metabolic models and provided supporting evidence of mitochondrial dysfunction related to the pathophysiologic mechanisms of AD progression. Subsequently, we investigated, in an animal model of AD, the oral administration of Combined Metabolic Activators (CMAs), consisting of NAD+ and glutathione precursors, to explore the effect for improvement of biological functions in AD. CMAs includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate, salt form of L-carnitine. The study revealed that supplementation of the CMAs improved the AD-associated histological parameters in the animals. Finally, we designed a randomized, double-blinded, placebo-controlled human phase 2 study and showed that the administration of CMAs improves cognitive functions in AD patients. A comprehensive analysis of the human plasma metabolome and proteome revealed that plasma levels of proteins and metabolites associated with redox metabolism are significantly improved after treatment. In conclusion, our results show that treating AD patients with metabolic activators leads to enhanced cognitive functions, suggesting a role for such a therapeutic regime in treating AD and other neurodegenerative diseases.

show abstract

Section: Discussionsupporting

confidence: 74%

Combined Metabolic Activators Improves Cognitive Functions in Alzheimer’s Disease

Yuluğ

Altay

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The largest metabolic analysis performed on urine of AD and MCI patients have permitted to shape a urinary metabolic phenotyping. Urine contains metabolites that reflect a response to injury, including OS, occurring at high distance or carry information originated from the gut microbiome, a novel area of research in neurodegeneration and AD [ 138 ]. The strength of this report, even if not specific on oxidative markers, lies in the potential to shape a metabolic profile associated with AD and to correlate such metabolites to genetic variants [ 138 ].…”

Section: Products Of Oxidative Damage In Blood Csf and Other Body Fluids Of Ad Patientsmentioning

confidence: 99%

“…Urine contains metabolites that reflect a response to injury, including OS, occurring at high distance or carry information originated from the gut microbiome, a novel area of research in neurodegeneration and AD [ 138 ]. The strength of this report, even if not specific on oxidative markers, lies in the potential to shape a metabolic profile associated with AD and to correlate such metabolites to genetic variants [ 138 ]. Peña-Bautista and colleagues have recently developed some analytical methods to determine a panel of lipid peroxidation biomarkers in urine, plasma, and saliva samples [ 25 , 138 , 139 , 140 , 141 , 142 , 143 , 144 ].…”

Section: Products Of Oxidative Damage In Blood Csf and Other Body Fluids Of Ad Patientsmentioning

confidence: 99%

“…The strength of this report, even if not specific on oxidative markers, lies in the potential to shape a metabolic profile associated with AD and to correlate such metabolites to genetic variants [ 138 ]. Peña-Bautista and colleagues have recently developed some analytical methods to determine a panel of lipid peroxidation biomarkers in urine, plasma, and saliva samples [ 25 , 138 , 139 , 140 , 141 , 142 , 143 , 144 ]. Saliva is also considered a promising source of biomarkers which measure products of oxidative damage.…”

Section: Products Of Oxidative Damage In Blood Csf and Other Body Fluids Of Ad Patientsmentioning

confidence: 99%

See 1 more Smart Citation

Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

et al. 2021

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

show abstract

“…Metabolomics is expected to provide new insights into biomarkers for the diagnosis and prognosis of AD [ 27 , 77 , 85 ]. As a conventional metabolomics research object, urine has also been analysed in metabolomics studies of AD, and characteristic urinary metabolites were identified and considered potential biomarkers of AD [ 36 , 83 ]. The analysis technology based on gas chromatography-mass spectrometry (GC–MS) with high sensitivity, high resolution and high reproducibility has been widely used in metabolomics studies.…”

Section: Introductionmentioning

confidence: 99%

Urinary metabolomic changes and microbiotic alterations in presenilin1/2 conditional double knockout mice

Gao

Zhou

et al. 2021

J Transl Med

View full text Add to dashboard Cite

Background Given the clinical low efficient treatment based on mono-brain-target design in Alzheimer’s disease (AD) and an increasing emphasis on microbiome-gut-brain axis which was considered as a crucial pathway to affect the progress of AD along with metabolic changes, integrative metabolomic signatures and microbiotic community profilings were applied on the early age (2-month) and mature age (6-month) of presenilin1/2 conditional double knockout (PS cDKO) mice which exhibit a series of AD-like phenotypes, comparing with gender and age-matched C57BL/6 wild-type (WT) mice to clarify the relationship between microbiota and metabolomic changes during the disease progression of AD. Materials and methods Urinary and fecal samples from PS cDKO mice and gender-matched C57BL/6 wild-type (WT) mice both at age of 2 and 6 months were collected. Urinary metabolomic signatures were measured by the gas chromatography-time-of-flight mass spectrometer, as well as 16S rRNA sequence analysis was performed to analyse the microbiota composition at both ages. Furthermore, combining microbiotic functional prediction and Spearman’s correlation coefficient analysis to explore the relationship between differential urinary metabolites and gut microbiota. Results In addition to memory impairment, PS cDKO mice displayed metabolic and microbiotic changes at both of early and mature ages. By longitudinal study, xylitol and glycine were reduced at both ages. The disturbed metabolic pathways were involved in glycine, serine and threonine metabolism, glyoxylate and dicarboxylate metabolism, pentose and glucuronate interconversions, starch and sucrose metabolism, and citrate cycle, which were consistent with functional metabolic pathway predicted by the gut microbiome, including energy metabolism, lipid metabolism, glycan biosynthesis and metabolism. Besides reduced richness and evenness in gut microbiome, PS cDKO mice displayed increases in Lactobacillus, while decreases in norank_f_Muribaculaceae, Lachnospiraceae_NK4A136_group, Mucispirillum, and Odoribacter. Those altered microbiota were exceedingly associated with the levels of differential metabolites. Conclusions The urinary metabolomics of AD may be partially mediated by the gut microbiota. The integrated analysis between gut microbes and host metabolism may provide a reference for the pathogenesis of AD.

show abstract

Urinary metabolic phenotyping for Alzheimer’s disease

Cited by 37 publications

References 91 publications

Combined Metabolic Activators Improves Cognitive Functions in Alzheimer’s Disease

Combined Metabolic Activators Improves Cognitive Functions in Alzheimer’s Disease

Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

Urinary metabolomic changes and microbiotic alterations in presenilin1/2 conditional double knockout mice

Contact Info

Product

Resources

About