Inflammatory Blood Biomarker Kynurenine Is Linked With Elevated Neuroinflammation and Neurodegeneration in Older Adults: Evidence From Two 1H-MRS Post-Processing Analysis Methods

Abstract

Rationale and ObjectivesPro-inflammatory processes have been argued to play a role in conditions associated with cognitive decline and neurodegeneration, like aging and obesity. Only a limited number of studies have tried to measure both peripheral and central biomarkers of inflammation and examined their interrelationship. The primary aim of this study was to examine the hypothesis that chronic peripheral inflammation would be associated with neurometabolic changes that indicate neuroinflammation (the combined elevation of myoinositol and choline), brain gray matter volume decrease, and lower cognitive functioning in older adults.Materials and MethodsSeventy-four older adults underwent bio-impedance body composition analysis, cognitive testing with the Montreal Cognitive Assessment (MoCA), blood serum analysis of inflammatory markers interleukin-6 (IL-6) and kynurenine, magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS) of the brain. Neurometabolic findings from both Tarquin and LCModel 1H-MRS post-processing software packages were compared. The regions of interest for MRI and 1H-MRS measurements were dorsal posterior cingulate cortex (DPCC), left hippocampal cortex (HPC), left medial temporal cortex (MTC), left primary sensorimotor cortex (SM1), and right dorsolateral prefrontal cortex (DLPFC).ResultsElevated serum kynurenine levels were associated with signs of neuroinflammation, specifically in the DPCC, left SM1 and right DLPFC, and signs of neurodegeneration, specifically in the left HPC, left MTC and left SM1, after adjusting for age, sex and fat percentage (fat%). Elevated serum IL-6 levels were associated with increased Glx levels in left HPC, left MTC, and right DLPFC, after processing the 1H-MRS data with Tarquin. Overall, the agreement between Tarquin and LCModel results was moderate-to-strong for tNAA, tCho, mIns, and tCr, but weak to very weak for Glx. Peripheral inflammatory markers (IL-6 and kynurenine) were not associated with older age, higher fat%, decreased brain gray matter volume loss or decreased cognitive functioning within a cohort of older adults.ConclusionOur results suggest that serum kynurenine may be used as a peripheral inflammatory marker that is associated with neuroinflammation and neurodegeneration, although not linked to cognition. Future studies should consider longitudinal analysis to assess the causal inferences between chronic peripheral and neuroinflammation, brain structural and neurometabolic changes, and cognitive decline in aging.

Neurometabolic correlates of posturography in normal aging and older adults with mild cognitive impairment: Evidence from a 1H-MRS study

“…Participants were 68 (37 females and 31 males), apparently healthy, older adults aged 60–85 years that were recruited from the same pool of participants as in Vints et al (2022) . The experimental protocol was approved by the local Medical Ethics Committee for Biomedical Research (No.…”

“…Specifically, low tNAA/tCr and elevated mIns/tCr and tCho/tCr in posterior cingulate cortex and/or hippocampus were reported as early predictors of transition from MCI to Alzheimer’s disease ( Liu et al, 2021 , Zhao et al, 2021 ). Finally, elevated levels of mIns in hippocampus and high levels of tCho and glutamate in the anterior cingulate cortex were found to be associated with worse performance on a working memory task as well as elevated low-grade systemic inflammation ( Lind et al, 2021 , Vints et al, 2022 ). Therefore, examining associations between postural stability and neurometabolite levels in key brain regions involved in balance control can shed light on processes that may lead to balance instability in older adults with MCI who are at high risk for falls and fall-related injuries ( Liu-Ambrose et al, 2008 ).…”

“…For example, changes in the regional levels of N -acetylaspartate/ N -acetyl-aspartyl-glutamate complex (tNAA), choline-phosphorylcholine-glycerophosphorylcholine complex (tCho), myo-inositol (mIns), gamma-aminobutyric acid (GABA), and glutamate-glutamine complex (Glx) which can be monitored in-vivo with proton-magnetic resonance spectroscopy ( 1 H-MRS), have been identified as potential biomarkers of disease progression in neurodegenerative disorders and dementia ( Ben Salem et al, 2008 , Ding et al, 2008 , Kantarci et al, 2007 ; Weerasekera et al, 2018; Zanigni et al, 2015 ). In healthy human volunteers, in-vivo quantification of brain neurometabolites with 1 H-MRS typically shows age-related declines in regional levels of multiple neurometabolites, including NAA, Glx, and GABA and increases in the levels of Cho and mIns ( Ding et al, 2016 , Gao et al, 2013 , Levin et al, 2019 , Porges et al, 2017 , Reyngoudt et al, 2012 , Vints et al, 2022 , Wijtenburg et al, 2013 , Zahr et al, 2013 ). For example, lower concentrations of NAA and Glx in sensorimotor cortex and lower Glx in the striatum were found to be strong predictors of performance declines on a variety of motor and cognitive tests performed by apparently healthy older adults ( Levin et al, 2019 , Weerasekera et al, 2020 , Zahr et al, 2008 , Zahr et al, 2013 ).…”

“…We focused specifically on possible associations between balance performance and expressions of tNAA/tCr tCho/tCr and mIns/tCr in hippocampus, hippocampal gyrus, posterior cingulate cortex, sensorimotor cortex, and prefrontal cortex. We hypothesized that (1) lower tNAA/tCr and elevated tCho/tCr and mIns/tCr, which are considered as biomarkers of neurodegeneration and neuroinflammation, respectively (e.g., Lind et al, 2020 , Liu et al, 2021 , Vints et al, 2022 , Zhao et al, 2021 ), would be related to reduced balance performance in general. Moreover, we hypothesized that (2) specific neurometabolic markers of neurodegeneration (tNAA/tCr) and neuroinflammation (mIns/tCr and tCho/tCr) in the hippocampus would predict worse balance performance of older individuals with MCI more than normative older adults.…”

Exercise-induced modulation of myokine irisin in bone and cartilage tissue—Positive effects on osteoarthritis: A narrative review

“…Elevated inflammatory markers in serum are thought to be associated with aging, obesity, and chronic disease. Chronic peripheral inflammation may cause neurodegenerative lesions (Vints et al, 2022). Irisin is often thought to be an exerciseprotective myokine that acts as an inflammatory resistance factor against inflammatory factors, used to reveal a possible link between exercise and the prevention of chronic disease (Martinez et al, 2018).…”