Do glia provide the link between low‐grade systemic inflammation and normal cognitive ageing? A ¹H magnetic resonance spectroscopy study at 7 tesla

Abstract

Low‐grade systemic inflammation contributes to ageing‐related cognitive decline, possibly by triggering a neuroinflammatory response through glial activation. Using proton magnetic resonance spectroscopy (1H‐MRS) at 7T in normal human individuals from 18 to 79 years in a cross‐sectional study, we previously observed higher regional levels of myo‐inositol (mIns), total creatine (tCr) and total choline (tCho) in older than younger age groups. Moreover, visuo‐spatial working memory (vsWM) correlated negatively with tCr and tCho in anterior cingulate cortex (ACC) and mIns in hippocampus and thalamus. As mIns, tCr and tCho are higher in glia than neurons, this suggest a potential in vivo connection between cognitive ageing and higher regional levels of glia‐related metabolites. In the present study, we tested whether these metabolic differences may be related to low‐grade systemic inflammation. In the same individuals, plasma concentrations of the proinflammatory markers C‐reactive protein (CRP), interleukin 8 (IL‐8), and tumour necrosis factor α (TNF‐α) were measured on the same day as 1H‐MRS assessments. We tested whether CRP, IL‐8, and TNF‐α concentrations correlated with the levels of glia‐related metabolites. CRP and IL‐8, but not TNF‐α, were higher in older (69–79 years) than younger (18–26 years) individuals. CRP correlated positively with thalamic mIns and negatively with vsWM. IL‐8 correlated positively with ACC tCho and hippocampal mIns, but not with vsWM. Mediation analysis revealed an indirect effect of IL‐8 on vsWM via ACC tCho. Together, these findings corroborate the role of glial cells, perhaps via their role in neuroinflammation, as part of the neurobiological link between systemic inflammation and cognitive ageing.

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

“…Thirdly, we test the hypothesis that higher levels of peripheral inflammation are associated with brain volume loss, and eventually our study's primary endpoint that peripheral inflammation is associated with neurometabolic changes indicating brain inflammation. This investigation elaborates the findings of Lind et al ( 45 ), since we used different peripheral serum biomarkers, added brain GMV measurements, examined more brain regions with 1 H-MRS, and used the MoCA as a more general screening instrument for mild cognitive impairment in older adults. Furthermore, we took into account the effect of age, fat%, and sex and excluded subjects with neurological and psychiatric disorders.…”

“…Moreover, it has been suggested that elevated levels of mIns or mIns/tCr are an early event in the course toward Alzheimer's dementia and can precede tNAA reduction ( 75 ). The previous studies have also reported a positive correlation between pro-inflammatory factors, IL-8 ( 45 ) or CRP ( 76 ) and hippocampal mIns levels after processing the 1 H-MRS data with the LCModel ( 45 ) or in a study where the 1 H-MRS post-processing analytical method was not defined ( 76 ). In our study, we did not find a significant relationship between one of the measured pro-inflammatory factors and mIns levels in the hippocampus with either of the post-processing software packages.…”

“…Firstly, in a previous study, they used proton magnetic resonance spectroscopy ( 1 H-MRS) to search for signs of neuroinflammation and discovered a link between cognitive aging and elevated levels of the glia-related neurometabolites, total choline (tCho), myoinositol (mIns), and total creatine (tCr) in the anterior cingulate cortex, hippocampus, and thalamus. Secondly, Lind et al ( 45 ) correlated these findings to blood levels of the pro-inflammatory markers C-reactive protein (CRP), interleukin-8 (IL)-8, and tumor necrosis factor-α (TNF-α) in young, middle-aged, and older adults. They reported that circulating levels of CRP and IL-8 were elevated in older adults.…”

Effects of ibudilast on central and peripheral markers of inflammation in alcohol use disorder: A randomized clinical trial

“…MRS was performed to assess in vivo markers thought to measure neuroinflammation (Cho, MI and Cr) and neuronal injury (NAA), in cerebral cortex and white matter. 25,26 We hypothesized that ibudilast would decrease peripheral markers of inflammation and increase peripheral markers of anti-inflammation and that participants treated with ibudilast would show lower levels of putative pro-inflammatory neurometabolites and higher levels of antiinflammatory NAA compared to placebo. This study also explored the predictive relationship of neurometabolite markers and subsequent drinking in the trial.…”

“…Proton magnetic resonance spectroscopy (MRS) allows for the non‐invasive detection of neurometabolites in vivo. Several neurometabolites are thought to serve as markers of neuroinflammation 25,26 . These include myo ‐inositol (MI), a glial marker primarily found in grey matter; choline‐containing compounds (Cho), a marker for cell membrane metabolism and turnover primarily found in white matter; and creatine + phosphocreatine (Cr), a marker for energy reserves of neurons and glia 25 .…”