CSF Cytokines in Aging, Multiple Sclerosis, and Dementia

Abstract

Inflammation is a common process involved in aging, multiple sclerosis (MS), and age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), but there is limited evidence for the effects of aging on inflammation in the central nervous system. We collected cerebrospinal fluid (CSF) from 105 healthy control subjects representing a wide age range (23–86), and analyzed levels of cytokines associated innate immunity (TNF-α) and different T-helper subtypes: interferon–gamma induced protein 10 (IP-10) for Th1, interleukin-10 (IL-10) for Th2, and interleukin 8 (IL-8/CXCL8) for Th17. We show that CSF levels of TNF-α, IP-10, and IL-8 all increased linearly with age, but levels of IL-10 demonstrated a U-shaped relationship with age. We further found greater age-related increases in TNF-α, IL-10, and IL-8 relative to increases in IP-10 levels, consistent with a shift from Th1 to other inflammatory phenotypes. Finally, when we analyzed the same four cytokines in people with neurological disorders, we found that MS and AD, but not PD or dementia with Lewy bodies, further accentuated the age-related shift from Th1- to non-Th1-related cytokines. We propose that CSF cytokine levels represent powerful surrogates of brain inflammation and aging, and some, but not all, neurological disorders accelerate the shift away from Th1 phenotypes.

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

“…Harmful A1 astroglial signature has been found also in the physiologically aged brain, and, interestingly, it was prevented in knockout mice with genetic ablation of the three microglial factors required for astrocytic A1 polarization, including TNF [ 99 ]. These results are coherent with a previously observed increase in basal TNF production by senescent microglia during aging [ 100 ], which may be involved in progressive cognitive impairment and predisposition to neurological disorders [ 101 ].…”

Linked CSF reduction of phosphorylated tau and IL-8 in HIV associated neurocognitive disorder

“…This is especially relevant to resolve conflicting findings on absolute cytokine levels from different studies (Table 2) 20,30 . To do so, we first converted each individual’s IL-8 and IP-10 levels into Z-scores (using NC young and NC older as the normative) to allow for easier comparison of two cytokines’ effect sizes according to each standard deviation alteration 31,32 . We then examined, within each individual, IL-8 and IP-10 levels relative to each other by difference between the two Z-scores (IL-8 and IP-10) 33 .…”

Cerebrospinal Fluid Levels of Interleukin-8 in Delirium, Dementia, and Cognitively Healthy Patients

“…They also showed that IL-1β levels negatively correlates with MMSE score and suggested that pro-inflammatory markers such as IL-1β and IL-8 may have separate pathogenic mechanisms involved in AD [55]. Moreover, IL-8 levels have also been reported to be elevated in CSF samples of AD patients [51,56,57] and this contradiction in the literature may well be due to the difference in sensitivity and robustness of the assay used and/or difference in patient cohorts in terms of pathology. Although, there was no significant difference observed in IL-8 levels between dementia and dementia free hip fracture patients (supplementary table 2).…”