Development of a blood‐based biomarker signature for detection of cognitive impairment through a targeted metabolomics approach deciphering the association with depression

AbstractBackgroundA series of pathological episodes set off the development of cognitive impairment, which precede years before the onset of clinical symptoms. Disrupted glucose and fatty acid metabolism notably contributes to the development of cognitive impairment and further advancement to clinical dementia. Disrupted metabolism leads to the secretion of various inflammatory eicosanoids leading to neuroinflammation. Alteration of some specific metabolites in plasma are noted during these metabolic changes. Depression is a key risk factor of cognitive impairment, and similar changes in plasma metabolites have observed in the pathophysiology of depression. This aim of this project is to establish a blood‐based biomarker signature for early detection of cognitive impairment in individuals with depression through quantifying plasma levels of metabolites associated with glucose and fatty acid metabolism in plasma samples from the participants of the Sydney Memory and Ageing Study (MAS).MethodSamples of 275 participants were randomly collected from baseline and 251 from an 8 year follow up study. At baseline there were 130 healthy participants, 93 participants with MCI, 36 participants with depression and 16 participants had both MCI and depression. Plasma samples were analysed to quantify the levels of fatty acids and carnitines using chemical derivatization – UPLC‐MRM/MS.ResultSignificant correlations were observed between the biomarkers like FA040 butyric acid (P: 0.034), FA224 (P: 0.032), acotinic acid (P:0.027) with MMSE. Biomarkers like C70carnitine (P:0.010), C90carnitine (P: 0.033), C150carnitine (P: 0.016), C160 carnitines (P: 0.004) significantly correlated with GDS scales. Linear regression showed significance between C90 carnitine (P: 0.021; β: 0.139) ad GDS scale. Whereas linear regression showed significant relationship between FA224 (P: 040, β: ‐.122), acotinic acid (P: 0.042, β: ‐.122), FA040 butyric acid (P: 0.036, β: ‐.193) with MMSE indicative of cognitive impairment.ConclusionThe study will help to identify candidate metabolites of perturbed fatty acid metabolism and establish a plasma biomarker signature of early cognitive impairment, by deciphering the association with depression as a risk factor. An association will be established between central AD pathology and peripheral metabolic changes, and potential treatment options targeting the right biochemical pathways will be identified.