Investigating Associations Between Inflammatory Biomarkers, Gray Matter, Neurofilament Light and Cognitive Performance in Healthy Older Adults

Abstract

Background: Exploring biological variables that may serve as indicators of the development and progression of cognitive decline is currently a high-priority research area. Recent studies have demonstrated that during normal aging, individuals experience increased inflammation throughout the brain and body, which may be linked to cognitive impairment and reduced gray matter volume in the brain. Neurofilament light polypeptide (NfL), which is released into the circulation following neuronal damage, has been proposed as a biomarker for neurodegenerative diseases, and may also have utility in the context of normal aging. The present study tested associations between age, peripheral levels of the pro-inflammatory cytokine IL-6, peripheral NfL, brain volume, and cognitive performance in a sample of healthy adults over 60 years old.Methods: Of the 273 individuals who participated in this study, 173 had useable neuroimaging data, a subset of whom had useable blood data (used for quantifying IL-6 and NfL) and completed a cognitive task. Gray matter (GM) thickness values were extracted from brain areas of interest using Freesurfer. Regression models were used to test relationships between IL-6, NfL, GM, and cognitive performance. To test putative functional relationships between these variables, exploratory path analytic models were estimated, in which the relationship between age, IL-6, and working memory performance were linked via four different operationalizations of brain health: (1) a latent GM variable composed of several regions linked to cognitive impairment, (2) NfL alone, (3) NfL combined with the GM latent variable, and (4) the hippocampus alone.Results: Regression models showed that IL-6 and NfL were significantly negatively associated with GM volume and that GM was positively associated with cognitive performance. The path analytic models indicated that age and cognitive performance are linked by GM in the hippocampus as well as several other regions previously associated with cognitive impairment, but not by NfL alone. Peripheral IL-6 was not associated with age in any of the path models.Conclusions: Results suggest that among healthy older adults, there are several GM regions that link age and cognitive performance. Notably, NfL alone is not a sufficient marker of brain changes associated with aging, inflammation, and cognitive performance.

Cardiometabolic state links neurovascular burden with brain structure and function across age: evidence from EEG and MRI

“…Indeed, chronic allostatic dysregulation, as indicated by a high ALI, triggers an exaggerated stress response within the brain, marked by the release of glucocorticoids, catecholamines, and proinflammatory cytokines leading to brain gray matter atrophy (Kline & Mega, 2020;Lenart-Bugla et al, 2022) as well as ventricular enlargement (McEwen, 2006(McEwen, , 2016. Consistently, allostatic overload-driven inflammatory states have been implicated in brain atrophy in hippocampal and prefrontal areas (Karoly et al, 2021;Lowther MK et al, 2020;Marsland et al, 2008;Schmidt MF et al, 2016) as well as increased WMHs (Nam et al, 2022;Raz et al, 2012), while also affecting brain electrophysiological dynamics (Düsing et al, 2016;Marshall & Cooper, 2017). Although the above evidence illustrates the associations between ALI and structural, neurovascular, and neurofunctional aspects, no consistent evidence of mechanisms linking these factors exists.…”

JNK‐IN‐8 treatment improves ARDS‐induced cognitive impairment by inhibiting JNK/NF‐κB‐mediated NLRP3 inflammasome

“…Previous studies have revealed that inflammation plays a critical role in the pathological course of ARDS (Bo et al., 2021; Tirunavalli et al., 2021) and cognitive impairment (Karoly et al., 2021; Kempuraj et al., 2020; Wang et al., 2020). Typical inflammatory pathways, such as the c‐Jun N‐terminal kinase (JNK)/nuclear factor (NF)‐κB (Bo et al., 2021; Xu et al., 2021; Yamamoto et al., 2021) and PI3K/Akt (Mizuta et al., 2020; Xue et al., 2021) pathways, are involved in the pathological processes of ARDS and nerve diseases.…”

“…Trauma (Kempuraj et al., 2020), surgery (Wang et al., 2020), and infection (Ermis et al., 2021) can trigger inflammation, resulting in cognitive dysfunction. Interleukin (IL)‐6, an inflammatory biomarker, and neurofilament light are negatively associated with cognitive function and gray matter volume in older adults (Karoly et al., 2021). Moreover, inflammation‐associated proteins, such as tumor necrosis factor‐α (TNF‐α) (Terrando et al., 2010) and IL‐1 (Cibelli et al., 2010), trigger postoperative neuroinflammation and cognitive dysfunction by activating inflammatory molecules, such as NF‐κB and mitogen‐activated protein kinases, in the cytoplasm.…”

Circulating Neurofilament Light Chain Levels Increase with Age and Are Associated with Worse Physical Function and Body Composition in Men but Not in Women

“…[ 9 , 10 ]. In this sense, some studies have shown that blood levels of NFL increase with age and are associated with changes in cognitive function [ 11 , 12 ]. NFL has been proposed as a potential biomarker for various neurodegenerative diseases, such as AD, PD, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and traumatic brain injury [ 13 , 14 , 15 ].…”