Plasma biomarkers associated with ALS and their relationship to iron homeostasis

ArticleinMuscle & Nerve 42(1):95-103 · July 2010with8 Reads
DOI: 10.1002/mus.21625 · Source: PubMed
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complicated pathogenesis with variable presentation and disease progression. There is a critical need for a panel of biomarkers to provide clinicians and researchers with additional information. In this study, multiplex immunoassays were used to screen a number of cytokines, growth factors, and iron-related proteins. ALS patients had significantly higher plasma levels of L-ferritin and lower concentrations of transferrin when compared to healthy controls and together classified a test group of subjects with 82% accuracy. Duration of ALS symptoms correlated positively with levels of monocyte chemoattractant protein 1 (MCP-1) and negatively with levels of granulocyte-macrophage colony stimulating factor (GM-CSF). The biomarker profile suggests iron homeostasis is disrupted in ALS patients, and changes in ferritin and transferrin (Tf) appear to be indicators of ongoing inflammatory processes. The data demonstrate a plasma biomarker profile in ALS patients that may differ from published reports of cerebrospinal fluid biomarkers.
    • "Aebischer reported that the level of IFN-γ was increased in post-mortem tissues of the spinal cord from ALS patients in France [1]. Several studies reported the elevation of IFN-γ in CSF and serum of ALS patients compared to various control subjects [3,8,11]. In this study, we found not only the elevation of IFN-γ in CSF and serum in ALS patients compared to non-ALS patients but also a significant difference between the CSF and serum IFN-γ levels in ALS patients. "
    [Show abstract] [Hide abstract] ABSTRACT: To explore whether the levels of IFN-γ in cerebral spinal fluid (CSF) and serum are elevated in ALS patients and to analyze the correlations between the IFN-γ levels and disease progression. CSF and serum samples were obtained from 52 ALS patients and 31 non-ALS patients. The levels of IFN-γ in CSF and serum were assessed, and disease progression parameters, including the disease interval (months from onset, MFO), the revised ALS Functional Rating Scale (ALSFRS-r) score and the disease progression rate (DPR) were analyzed by registered neurologists. All samples were measured using a commercial enzyme-linked immunosorbent assay. Statistical analyses were performed using Prism software. Compared to the non-ALS patients, the ALS patients displayed significantly increased levels of IFN-γ in both CSF and serum, and these values consistently correlated with disease progression. These results demonstrated that IFN-γ in CSF may serve as a biomarker of ALS differentiation and progression. CSF IFN-γ was a more reliable biomarker of disease diagnosis and progression than serum IFN-γ.
    Full-text · Article · Sep 2015
    • "Some studies have identified some relevant clinical features [especially forced vital capacity (FVC), symptom duration and several items from the Revised ALS Functional Rating Scale (ALSFRS-R) score]234. Combinations of innovative biological markers, such as those derived from metabolomics [5] , proteo- mics [6] or multiplex immunoassays [7] , could be useful for diagnosis and might even predict ALS prognosis [8]. Similarly, amongst routinely evaluated biochemical markers, creatinine [9,10], ferritin [10,11] and lipid profile111213 may have prognostic value. "
    [Show abstract] [Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal disorder of the motor neuron system, with a median survival of 2 to 4 years and a wide variety of prognosis. Thus, there is a critical need for diagnosis and prognosis biomarkers to improve the care of patients in routine practice. In this study, we aimed to determine prognostic value of routine biochemical markers in sporadic ALS (SALS). We retrospectively collected clinical and biological data obtained during the systematic routine monitoring of 216 sporadic ALS patients. The main outcomes were disease duration and annual decline of Revised ALS Functional Rating Scale (ALSFRS-R). Changes to these biological variables over time were assessed, in link with disease progression. We found that concentrations of creatinine (P=0.0166) and ferritin (P=0.0306) changed significantly during the progression of ALS. A reduction of creatinine levels and an increase of ferritin levels were associated with disease progression. Multivariate analysis showed that early variation of ferritin was an independent predictive factor of patient survival (P=0.0048). Changes to ferritin and creatinine levels with time are associated with ALS progression. This is the first study describing the changes to these biological variables during ALS progression. © 2015 EAN.
    Article · Jun 2015
    • "Su et al. [30] showed that particular cytokines found in plasma of ALS patients predict shorter (IL-1β and IL-12) or longer (IL-10) disease duration and suggested that a lesser degree of inflammation might be associated with longer disease duration. However , it has been noted that biomarkers in plasma, mainly indicating ongoing inflammatory processes in ALS patients , might differ from CSF biomarkers [31]. Nitric oxide (NO), a gasotransmitter, has also been shown as a significant contributor in ALS pathogenesis by glutamate-induced neuronal death (reviewed in [32]). "
    [Show abstract] [Hide abstract] ABSTRACT: Amyotrophic 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. Thirteen 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. ALS 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. Our 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.
    Full-text · Article · Jun 2015
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