Metabolomic changes associated with frontotemporal lobar degeneration syndromes

Abstract

Objective Widespread metabolic changes are seen in neurodegenerative disease and could be used as biomarkers for diagnosis and disease monitoring. They may also reveal disease mechanisms that could be a target for therapy. In this study we looked for blood-based biomarkers in syndromes associated with frontotemporal lobar degeneration. Methods Plasma metabolomic profiles were measured from 134 patients with a syndrome associated with frontotemporal lobar degeneration (behavioural variant frontotemporal dementia n = 30, non fluent variant primary progressive aphasia n = 26, progressive supranuclear palsy n = 45, corticobasal syndrome n = 33) and 32 healthy controls. Results Forty-nine of 842 metabolites were significantly altered in frontotemporal lobar degeneration syndromes (after false-discovery rate correction for multiple comparisons). These were distributed across a wide range of metabolic pathways including amino acids, energy and carbohydrate, cofactor and vitamin, lipid and nucleotide pathways. The metabolomic profile supported classification between frontotemporal lobar degeneration syndromes and controls with high accuracy (88.1-96.6%) while classification accuracy was lower between the frontotemporal lobar degeneration syndromes (72.1-83.3%). One metabolic profile, comprising a range of different pathways, was consistently identified as a feature of each disease versus controls: the degree to which a patient expressed this metabolomic profile was associated with their subsequent survival (hazard ratio 0.74 [0.59-0.93], p = 0.0018). Conclusions The metabolic changes in FTLD are promising diagnostic and prognostic biomarkers. Further work is required to replicate these findings, examine longitudinal change, and test their utility in differentiating between FTLD syndromes that are pathologically distinct but phenotypically similar.

Blood metabolic fingerprinting of rats, subjected to subchronic lead exposure

“…This substance, in turn, provides apoptotic cell engulfment by macrophages 59 . Thus, increasing of LysoPS (22:6) concentration in exposed to lead group may serve as a marker of intensification of the apoptotic processes -this fact is also confirmed by the results of previous metabolomic investigations [60][61][62] .…”

Frontotemporal Dementia and Glucose Metabolism

“…Studies looking at the metabolic profile of FTD patients revealed dysregulation of glucose metabolism pathways on a more global scale ( Ahmed et al, 2014 ; Murley et al, 2020 ). When looking at sv-FTD and bhv-FTD patients’, the latter had lower high-density lipoprotein levels as well as increased total cholesterol levels compared to controls and both had increased triglyceride levels ( Ahmed et al, 2014 ).…”

“…Moreover, A study involving 134 FTD patients analyzed 842 plasma metabolites and identified 49 differently altered metabolites compared to controls among FTD patients, seven were involved in energy production or carbohydrate pathways ( Murley et al, 2020 ). Observations included reduced levels of the glycolysis end product pyruvate, the TCAC intermediate succinate, glycerol-3-phosphate (a molecule pertinent to NADH re-oxidation) and glucogenic amino acids ( Murley et al, 2020 ). Whilst the first three results indicate reduced glucose metabolism activity, the last finding may point to a compensatory mechanism resulting from reduced glucose intake by cells ( Wilkins and Trushina, 2018 ; Murley et al, 2020 ).…”

“…Observations included reduced levels of the glycolysis end product pyruvate, the TCAC intermediate succinate, glycerol-3-phosphate (a molecule pertinent to NADH re-oxidation) and glucogenic amino acids ( Murley et al, 2020 ). Whilst the first three results indicate reduced glucose metabolism activity, the last finding may point to a compensatory mechanism resulting from reduced glucose intake by cells ( Wilkins and Trushina, 2018 ; Murley et al, 2020 ). Simultaneously, elevated levels of the commonplace polysaccharide’s maltose and maltotetraose were recorded.…”

Fluid biomarkers in frontotemporal dementia: past, present and future

“…It is likely that such studies will take place within the context of large cohort studies [see Box 6] avoiding the problems of small sample sizes that are inherent to so many of the published papers so far. Such studies will also pave the way for larger -omics studies which have so far been relatively small and focused on proteomics despite initial evidence for abnormalities in metabolomics [134][135][136] and lipidomics [137][138][139] in FTD as well.…”