Humoral factors in ALS patients during disease progression

Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons in the CNS and leading to paralysis and death. There are currently no effective treatments for ALS due to the complexity and heterogeneity of factors involved in motor neuron degeneration. A complex of interrelated effectors have been identified in ALS, yet systemic factors indicating and/or reflecting pathological disease developments are uncertain. The purpose of the study was to identify humoral effectors as potential biomarkers during disease progression.MethodsThirteen clinically definite ALS patients and seven non-neurological controls enrolled in the study. Peripheral blood samples were obtained from each ALS patient and control at two visits separated by 6 months. The Revised ALS Functional Rating Scale (ALSFRS-R) was used to evaluate overall ALS-patient functional status at each visit. Eleven humoral factors were analyzed in sera. Cytokine levels (GM-CSF, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-α) were determined using the Bio-Rad Bio-Plex® Luminex 200 multiplex assay system. Nitrite, a breakdown product of NO, was quantified using a Griess Reagent System. Glutathione (GSH) concentrations were measured using a Glutathione Fluorometric Assay Kit.ResultsALS patients had ALSFRS-R scores of 30.5 ± 1.9 on their first visit and 27.3 ± 2.7 on the second visit, indicating slight disease progression. Serum multiplex cytokine panels revealed statistically significant changes in IL-2, IL-5, IL-6, and IL-8 levels in ALS patients depending on disease status at each visit. Nitrite serum levels trended upwards in ALS patients while serum GSH concentrations were drastically decreased in sera from ALS patients versus controls at both visits.ConclusionsOur results demonstrated a systemic pro-inflammatory state and impaired antioxidant system in ALS patients during disease progression. Increased levels of pro-inflammatory IL-6, IL-8, and nitrite and significantly decreased endogenous antioxidant GSH levels could identify these humoral constituents as systemic biomarkers for ALS. However, systemic changes in IL-2, IL-5, and IL-6 levels determined between visits in ALS patients might indicate adaptive immune system responses dependent on current disease stage. These novel findings, showing dynamic changes in humoral effectors during disease progression, could be important for development of an effective treatment for ALS.

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

“…Similar to the results in CSF, increases in levels of inflammatory factors (IL-6 and IL-8) were also observed [134]. However, in contrast to levels in the CSF, decreases in immune factors (IL-5 and IL-2) and glutathione levels were also shown indicating decreased immune response with increased oxidative stress.…”

Chemokine Interleukin-8 (IL-8) in Alzheimer’s and Other Neurodegenerative Diseases

“…The authors suggested that the elevation in IL-8 was mediated by activated microglia leading to a pro-inflammatory cascade in ALS brain. Levels of cytokines and chemokines have been measured in peripheral blood samples taken from ALS patients and controls [24]. A number of inflammatory mediators including IL-8 exhibited significant increases in blood from ALS individuals.…”

Evaluating the levels of CSF and serum factors in ALS

“…Some studies were limited by the number of samples in the analysis (Turner et al., 2013), and some chose a different control population into the study (Tateishi et al., 2010). In addition, a panel of biomarkers has been detected in either the CSF or serum in some recent studies, but they were either more concerned with a diagnosis rather than a clinically relevant prognosis (Gray et al., 2015; Kuhle et al., 2009; Lawton et al., 2012) or only measuring factors either the CSF or serum (Ehrhart et al., 2015; Mitchell et al., 2009). …”